Saccharide protective coating for pharmaceutical package

ABSTRACT

A method for providing a saccharide based lubricating or protective coating or layer on a substrate surface is provided. In particular, a lubricity and/or protective coating or layer made by said method is provided. Pharmaceutical packages or other vessels coated by said method and the use of such pharmaceutical packages or other vessels protecting a compound or composition contained or received in said vessel with a protective coating against mechanical and/or chemical effects of the surface of the vessel without a protective coating material are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase of International Application No. PCT/US2013/040380 filed May 9, 2013, which claims priority to U.S. Provisional Patent Application No, 61/644,961 filed May 9, 2012, which are incorporated herein by reference in their entirety.

The priority of U.S. Provisional Ser. No. 61/644,961, filed May 9, 2012, is claimed. That patent application is incorporated here by reference in its entirety.

U.S. Provisional Ser. Nos. 61/177,984 filed May 13, 2009; 61/222,727, filed Jul. 2, 2009; 61/213,904, filed Jul. 24, 2009; 61/234,505, filed Aug. 17, 2009; 61/261,321, filed Nov. 14, 2009; 61/263,289, filed Nov. 20, 2009; 61/285,813, filed Dec. 11, 2009; 61/298,159, filed Jan. 25, 2010; 61/299,888, filed Jan. 29, 2010; 61/318,197, filed Mar. 26, 2010; 61/333,625, filed May 11, 2010; 61/413,334, filed Nov. 12, 2010; Ser. No. 12/779,007, filed May 12, 2010, now U.S. Pat. No. 7,985,188; International Application PCT/US11/36097, filed May 11, 2011; and U.S. Ser. No. 61/558,885, filed Nov. 11, 2011; are all incorporated here by reference in their entirety.

Also incorporated by reference in their entirety are the following European patent applications: EP10162755.2 filed May 12, 2010; EP10162760.2 filed May 12, 2010; EP10162756.0 filed May 12, 2010; EP10162758.6 filed May 12, 2010; EP10162761.0 filed May 12, 2010; and EP10162757.8 filed May 12, 2010. These European patent applications describe apparatus, vessels, precursors, coatings or layers and methods (in particular coating methods and test methods for examining the coatings or layers) which can generally be used in performing the present invention, unless stated otherwise herein. They also describe SiO_(x) barrier coatings or layers to which reference is made herein.

FIELD OF THE INVENTION

The present invention relates to the technical field of coated surfaces, for example interior surfaces of pharmaceutical packages or other vessels for storing or other contact with fluids. Examples of suitable fluids include foods or biologically active compounds or body fluids, for example blood. The present invention also relates to a pharmaceutical package or other vessel and to a method for coating an inner or interior surface of a pharmaceutical package or other vessel. The present invention also relates more generally to medical devices, including devices other than packages or vessels, for example catheters.

The present disclosure also relates to improved methods for processing pharmaceutical packages or other vessels, for example multiple identical pharmaceutical packages or other vessels used for pharmaceutical preparation storage and delivery, venipuncture and other medical sample collection, and other purposes. Such pharmaceutical packages or other vessels are used in large numbers for these purposes, and must be relatively economical to manufacture and yet highly reliable in storage and use.

BACKGROUND OF THE INVENTION

One important consideration in manufacturing pharmaceutical packages or other vessels for storing or other contact with fluids, for example vials and pre-filled syringes, is that the contents of the pharmaceutical package or other vessel desirably will have a substantial shelf life. During this shelf life, it is important to isolate the material filling the pharmaceutical package or other vessel from the vessel wall containing it, or from barrier layers or other functional layers applied to the pharmaceutical package or other vessel wall to avoid leaching material from the pharmaceutical package or other vessel wall, barrier layer, or other functional layers into the prefilled contents or vice versa.

Since many of these pharmaceutical packages or other vessels are inexpensive and used in large quantities, for certain applications it will be useful to reliably obtain the necessary shelf life without increasing the manufacturing cost to a prohibitive level.

For decades, most parenteral therapeutics have been delivered to end users in Type I medical grade borosilicate glass vessels such as vials or pre-filled syringes. The relatively strong, impermeable and inert surface of borosilicate glass has performed adequately for most drug products. However, the recent advent of costly, complex and sensitive biologics as well as such advanced delivery systems as auto injectors has exposed the physical and chemical shortcomings of glass pharmaceutical packages or other vessels, including possible contamination from metals, flaking, and breakage, among other problems. Moreover, glass contains several components which can leach out during storage and cause damage to the stored material. In more detail, borosilicate pharmaceutical packages or other vessels exhibit a number of drawbacks:

Glass is manufactured from sand containing a heterogeneous mixture of many elements (silicon, oxygen, boron, aluminum, sodium, calcium) with trace levels of other alkali and earth metals. Type I borosilicate glass consists of approximately 76% SiO₂, 10.5% B₂O₃, 5% Al₂O₃, 7% Na2O and 1.5% CaO and often contains trace metals such as iron, magnesium, zinc, copper and others. The heterogeneous nature of borosilicate glass creates a non-uniform surface chemistry at the molecular level. Glass forming processes used to create glass vessels expose some portions of the vessels to temperatures as great as 1200° C. Under such high temperatures alkali ions migrate to the local surface and form oxides. The presence of ions extracted from borosilicate glass devices may be involved in degradation, aggregation and denaturation of some biologics. Many proteins and other biologics must be lyophilized (freeze dried), because they are not sufficiently stable in solution in glass vials or syringes.

In glass syringes, silicon oil is typically used as a lubricant to allow the plunger to slide in the barrel. Silicon oil has been implicated in the precipitation of protein solutions such as insulin and some other biologics. Additionally, the silicon oil coating or layer is often non-uniform, resulting in syringe failures in the market.

Glass pharmaceutical packages or other vessels are prone to breakage or degradation during manufacture, filling operations, shipping and use, which means that glass particulates may enter the drug. The presence of glass particles has led to many FDA Warning Letters and to product recalls.

Glass-forming processes do not yield the tight dimensional tolerances required for some of the newer auto-injectors and delivery systems.

As a result, some companies have turned to plastic pharmaceutical packages or other vessels, which provide greater dimensional tolerance and less breakage than glass but lack its impermeability.

Although plastic is superior to glass with respect to breakage, dimensional tolerances and surface uniformity, its use for primary pharmaceutical packaging remains limited due to the following shortcomings:

-   -   Gas (oxygen) permeability: Plastic allows small molecule gases         to permeate into (or out of) the device. The permeability of         plastics to gases is significantly greater than that of glass         and, in many cases (as with oxygen-sensitive drugs such as         epinephrine), plastics have been unacceptable for that reason.     -   Water vapor transmission: Plastics allow water vapors to pass         through devices to a greater degree than glass. This can be         detrimental to the shelf life of a solid (lyophilized) drug.         Alternatively, a liquid product may lose water in an arid         environment.     -   Leachables and extractables: Plastic pharmaceutical packages or         other vessels contain organic compounds that can leach out or be         extracted into the drug product. These compounds can contaminate         the drug and/or negatively impact the drug's stability.

Clearly, while plastic and glass pharmaceutical packages or other vessels each offer certain advantages in pharmaceutical primary packaging, neither is optimal for all drugs, biologics or other therapeutics. Thus, there is a desire for plastic pharmaceutical packages or other vessels, in particular plastic syringes, with gas and solute barrier properties which approach the properties of glass. Moreover, there is a need for plastic syringes with sufficient lubricity and/or protective properties and a lubricity and/or protective coating or layer which is compatible with the syringe contents.

There are additional considerations to be taken into account when manufacturing a prefilled syringe. Prefilled syringes are commonly prepared and sold so the syringe does not need to be filled before use, and can be disposed of after use. The syringe can be prefilled with saline solution, a dye for injection, or a pharmaceutically active preparation, for some examples.

Commonly, the prefilled syringe is capped at the distal end, as with a cap, and is closed at the proximal end by its drawn plunger. The prefilled syringe can be wrapped in a sterile package before use. To use the prefilled syringe, the packaging and cap are removed, optionally a hypodermic needle or another delivery conduit is attached to the distal end of the barrel, the delivery conduit or syringe is moved to a use position (such as by inserting the hypodermic needle into a patient's blood vessel or into apparatus to be rinsed with the contents of the syringe), and the plunger is advanced in the barrel to inject the contents of the barrel.

An important consideration regarding medical syringes is to ensure that the plunger can move at a constant speed and with a constant force when it is pressed into the barrel. A similar consideration applies to vessels such as pharmaceutical vials which have to be closed by a stopper, and to the stopper itself, and more generally to any surface which has to provide smooth operation of moving parts and/or be protectively coated.

A non-exhaustive list of documents of possible relevance includes U.S. Pat. Nos. 7,901,783; 6,068,884; 4,844,986; and 8067070 and U.S. Publ. Appl. Nos. 2008/0090039, 2011/0152820, 2006/0046006 and 2004/0267194. These documents are all incorporated by reference.

SUMMARY OF THE INVENTION

An aspect of the invention is a filled package comprising a vessel, a barrier coating and a protective coating on the vessel, and a fluid composition contained in the vessel. The calculated shelf life of the package is more than six months at a storage temperature of 4° C.

The vessel has a lumen defined at least in part by a wall. The wall has an interior surface facing the lumen and an outer surface.

The barrier coating comprises SiO_(x), wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick. The barrier coating of SiO_(x) has an interior surface facing the lumen and an outer surface facing the wall interior surface. The barrier coating is effective to reduce the ingress of atmospheric gas into the lumen compared to an vessel without a protective coating.

The protective coating comprises a protective coating or layer of a saccharide. The protective coating has an interior surface facing the lumen and an outer surface facing the interior surface of the barrier coating. The protective coating is effective to increase the calculated shelf life of the package (total Si/Si dissolution rate).

The fluid composition is contained in the lumen and has a pH between 5 and 9.

Another aspect of the invention is a filled package comprising a vessel, a saccharide protective coating on the vessel, and a fluid composition contained in the vessel.

The vessel has a lumen defined at least in part by a wall. The wall has an interior surface comprising glass facing the lumen and an outer surface.

The protective coating comprises a protective coating or layer of a saccharide. The protective coating has an interior surface facing the lumen and an outer surface facing the interior surface of the barrier coating. The protective coating is effective to decrease the Si dissolution rate of the glass interior surface.

The fluid composition is contained in the lumen and has a pH between 5 and 9.

Still another aspect of the invention is an article comprising a wall, a barrier coating, and a saccharide protective coating.

The wall has a surface.

The barrier coating comprises SiO_(x), wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick. The barrier coating of SiO_(x) has an interior surface facing the lumen and an outer surface facing the wall interior surface. The barrier coating is effective to reduce the ingress of atmospheric gas through the wall compared to an uncoated wall.

The protective coating of any embodiment is on the barrier coating and comprises a protective coating or layer of a saccharide. The protective coating is contemplated to be formed by binding a coupling agent to the barrier coating, then binding the saccharide to the binding agent, either directly or through intermediate agents. Alternatively, the coupling agent can first be bound to the saccharide, then the saccharide-binder combination can be bonded to the barrier coating or layer.

The rate of erosion of the protective coating, if directly contacted by a fluid composition having a pH at some point between 5 and 9, is less than the rate of erosion of the barrier coating, if directly contacted by the fluid composition.

Even another aspect of the invention is a vessel comprising a wall, a fluid contained in the vessel, a barrier coating, and a protective coating.

The wall is a thermoplastic wall having an interior surface enclosing a lumen.

The fluid is disposed in the lumen and has a pH greater than 5.

The barrier coating comprises SiO_(x), in which x is between 1.5 and 2.9. The barrier coating is applied by PECVD. The barrier coating is positioned between the interior surface of the thermoplastic wall and the fluid, and supported by the thermoplastic wall. The barrier coating has the characteristic of being subject to being measurably diminished in barrier improvement factor in less than six months as a result of attack by the fluid.

The protective coating comprises a saccharide. The protective coating is positioned between the barrier coating and the fluid. The protective coating is supported by the thermoplastic wall. The protective coating is effective to keep the barrier coating at least substantially undissolved as a result of attack by the fluid for a period of at least six months.

Also expressly contemplated is a syringe having a barrel, a plunger movable axially in the barrel, and an O-ring or other toroidal band interfacing between the plunger and the barrel. It is contemplated that the O-ring will function to reduce the “sticktion” force preventing initial movement of the plunger in the barrel by rolling along the plunger and barrel when the plunger is first subjected to an advancing force.

Other aspects of the invention will become apparent to a person of ordinary skill in the art after reviewing the present disclosure and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic sectional view of a vessel holder in a coating station according to an embodiment of the disclosure.

FIG. 2 is a section taken along section lines A-A of FIG. 1.

FIG. 3 is a view similar to FIG. 1 of another embodiment for processing syringe barrels and other pharmaceutical packages or other vessels.

FIG. 4 is an enlarged detail view of the processing vessel of FIG. 3.

FIG. 5 is a schematic view of an assembly for treating pharmaceutical packages or other vessels. The assembly is usable with the apparatus in any of the preceding figures.

FIG. 6 shows a TEM image of an SiO₂ barrier coating or layer which is coated on a COC substrate.

FIG. 7 is an assembly view of a prefilled syringe provided with a barrier layer, a protective coating or layer, and a lubricity layer and filled and closed to provide a pharmaceutical package.

FIG. 8 is a schematic view of a pharmaceutical package in the form of a vial provided with a barrier layer, a protective coating or layer, and optionally a lubricity layer.

FIG. 9 is a schematic view of a pharmaceutical package in the form of a blister package provided with a barrier layer and a protective coating or layer.

The following reference characters are used in the drawing figures:

28 coating station 50 Vessel holder 80 Vessel 82 Opening 84 Closed end 86 Wall 88 Inner or interior surface 90 Barrier layer 92 Vessel port 94 Vacuum duct 96 Vacuum port 98 Vacuum source 100 O-ring (of 92) 102 O-ring (of 96) 104 Gas inlet port 106 O-ring (of 100) 108 Probe (counter electrode) 110 Gas delivery port (of 108) 114 Housing (of 50 or 112) 116 Collar 118 Exterior surface (of 80) 144 PECVD gas source 152 Pressure gauge 160 Electrode 162 Power supply 164 Sidewall (of 160) 166 Sidewall (of 160) 168 Closed end (of 160) 210 Pharmaceutical package 212 Lumen 214 Wall 216 Outer surface 218 Fluid composition 220 Interior surface (of 288) 222 Outer surface (of 288) 224 Interior surface (of 286) 226 Outer surface (of 286) 250 Syringe barrel 254 Inner or interior surface (of 250) 256 Back end (of 250) 258 Plunger (of 252) (relatively sliding part) 260 Front end (of 250) 262 Cap 264 Inner or interior surface (of 262) 286 protective coating 287 Lubricity layer 288 Barrier layer 290 Apparatus for coating, for example, 250 292 Inner or interior surface (of 294) 294 Restricted opening (of 250) 296 Processing vessel 298 Outer surface (of 250) 300 Lumen (of 250) 302 Larger opening (of 250) 304 Processing vessel lumen 306 Processing vessel opening 308 Inner electrode 310 Interior passage (of 308) 312 Proximal end (of 308) 314 Distal end (of 308) 316 Distal opening (of 308) 318 Plasma 332 First fitting (male Luer taper) 334 Second fitting (female Luer taper) 336 Locking collar (of 332) 338 First abutment (of 332) 340 Second abutment (of 332) 342 O-ring 344 Dog 574 Main vacuum valve 576 Vacuum line 578 Manual bypass valve 580 Bypass line 582 Vent valve 584 Main reactant gas valve 586 Main reactant feed line 588 Organosilicon liquid reservoir 590 Organosilicon feed line (capillary) 592 Organosilicon shut-off valve 594 Oxygen tank 596 Oxygen feed line 598 Mass flow controller 600 Oxygen shut-off valve 614 Headspace 616 Pressure source 618 Pressure line 620 Capillary connection

DETAILED DESCRIPTION

The present invention will now be described more fully, with reference to the accompanying drawings, in which several embodiments are shown. This invention can, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth here. Rather, these embodiments are examples of the invention, which has the full scope indicated by the language of the claims. Like numbers refer to like or corresponding elements throughout. The following disclosure relates to all embodiments unless specifically limited to a certain embodiment.

Definition Section

In the context of the present invention, the following definitions and abbreviations are used:

RF is radio frequency.

The term “at least” in the context of the present invention means “equal or more” than the integer following the term. The word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality unless indicated otherwise. Whenever a parameter range is indicated, it is intended to disclose the parameter values given as limits of the range and all values of the parameter falling within said range.

“First” and “second” or similar references to, for example, processing stations or processing devices refer to the minimum number of processing stations or devices that are present, but do not necessarily represent the order or total number of processing stations and devices. These terms do not limit the number of processing stations or the particular processing carried out at the respective stations.

For purposes of the present invention, an “organosilicon precursor” is a compound having at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). A volatile organosilicon precursor, defined as such a precursor that can be supplied as a vapor in a PECVD apparatus, is an optional organosilicon precursor. Optionally, the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors.

The feed amounts of PECVD precursors, gaseous reactant or process gases, and carrier gas are sometimes expressed in “standard volumes” in the specification and claims. The standard volume of a charge or other fixed amount of gas is the volume the fixed amount of the gas would occupy at a standard temperature and pressure (without regard to the actual temperature and pressure of delivery). Standard volumes can be measured using different units of volume, and still be within the scope of the present disclosure and claims. For example, the same fixed amount of gas could be expressed as the number of standard cubic centimeters, the number of standard cubic meters, or the number of standard cubic feet. Standard volumes can also be defined using different standard temperatures and pressures, and still be within the scope of the present disclosure and claims. For example, the standard temperature might be 0° C. and the standard pressure might be 760 Torr (as is conventional), or the standard temperature might be 20° C. and the standard pressure might be 1 Torr. But whatever standard is used in a given case, when comparing relative amounts of two or more different gases without specifying particular parameters, the same units of volume, standard temperature, and standard pressure are to be used relative to each gas, unless otherwise indicated.

The corresponding feed rates of PECVD precursors, gaseous reactant or process gases, and carrier gas are expressed in standard volumes per unit of time in the specification. For example, in the working examples the flow rates are expressed as standard cubic centimeters per minute, abbreviated as sccm. As with the other parameters, other units of time can be used, such as seconds or hours, but consistent parameters are to be used when comparing the flow rates of two or more gases, unless otherwise indicated.

A “vessel” in the context of the present invention can be any type of vessel with at least one opening and a wall defining an inner or interior surface. The substrate can be the inside wall of a vessel having a lumen. Though the invention is not necessarily limited to pharmaceutical packages or other vessels of a particular volume, pharmaceutical packages or other vessels are contemplated in which the lumen has a void volume of from 0.5 to 50 mL, optionally from 1 to 10 mL, optionally from 0.5 to 5 mL, optionally from 1 to 3 mL. The substrate surface can be part or all of the inner or interior surfaceinner or interior surface of a vessel having at least one opening and an inner or interior surfaceinner or interior surface.

The term “at least” in the context of the present invention means “equal or more” than the integer following the term. Thus, a vessel in the context of the present invention has one or more openings. One or two openings, like the openings of a sample tube (one opening) or a syringe barrel (two openings) are preferred. If the vessel has two openings, they can be of same or different size. If there is more than one opening, one opening can be used for the gas inlet for a PECVD coating method according to the present invention, while the other openings are either capped or open. A vessel according to the present invention can be a sample tube, for example for collecting or storing biological fluids like blood or urine, a syringe (or a part thereof, for example a syringe barrel) for storing or delivering a biologically active compound or composition, for example a medicament or pharmaceutical composition, a vial for storing biological materials or biologically active compounds or compositions, a pipe, for example a catheter for transporting biological materials or biologically active compounds or compositions, or a cuvette for holding fluids, for example for holding biological materials or biologically active compounds or compositions.

A vessel can be of any shape, a vessel having a substantially cylindrical wall adjacent to at least one of its open ends being preferred. Generally, the interior wall of the vessel is cylindrically shaped, like, for example in a sample tube or a syringe barrel. Sample tubes and syringes or their parts (for example syringe barrels) are contemplated.

A “lubricity and/or protective coating” according to the present invention is a coating or layer which has a lower frictional resistance than the uncoated surface, which is a lubricity layer, and/or protects an underlying surface or layer from a fluid composition contacting the layer, which is a protective coating or layer (as more extensively defined elsewhere in this specification). In other words, respecting a lubricity layer, it reduces the frictional resistance of the coated surface in comparison to a reference surface that is uncoated. The present lubricity and/or protective coatings are primarily defined as lubricity layers by their lower frictional resistance than the uncoated surface and the process conditions providing lower frictional resistance than the uncoated surface.

“Frictional resistance” can be static frictional resistance and/or kinetic frictional resistance.

One of the optional embodiments of the present invention is a syringe part, for example a syringe barrel or plunger, coated with a lubricity and/or protective coating. In this contemplated embodiment, the relevant static frictional resistance in the context of the present invention is the breakout force as defined herein, and the relevant kinetic frictional resistance in the context of the present invention is the plunger sliding force as defined herein. For example, the plunger sliding force as defined and determined herein is suitable to determine the presence or absence and the lubricity and/or protective characteristics of a lubricity and/or protective coating or layer in the context of the present invention whenever the coating or layer is applied to any syringe or syringe part, for example to the inner wall of a syringe barrel. The breakout force is of particular relevance for evaluation of the coating or layer effect on a prefilled syringe, i.e. a syringe which is filled after coating and can be stored for some time, for example several months or even years, before the plunger is moved again (has to be “broken out”).

The “plunger sliding force” (synonym to “glide force,” “maintenance force”, or Fm, also used in this description) in the context of the present invention is the force required to maintain movement of a plunger in a syringe barrel, for example during aspiration or dispense. It can advantageously be determined using the ISO 7886-1:1993 test described herein and known in the art. A synonym for “plunger sliding force” often used in the art is “plunger force” or “pushing force”.

The “plunger breakout force” (synonym to “breakout force”, “break loose force”, “initiation force”, Fi, also used in this description) in the context of the present invention is the initial force required to move the plunger in a syringe, for example in a prefilled syringe.

Both “plunger sliding force” and “plunger breakout force” and methods for their measurement are described in more detail in subsequent parts of this description. These two forces can be expressed in N, lbs or kg and all three units are used herein. These units correlate as follows: 1N=0.102 kg=0.2248 lbs (pounds).

Sliding force and breakout force are sometimes used herein to describe the forces required to advance a stopper or other closure into a pharmaceutical package or other vessel, such as a medical sample tube or a vial, to seat the stopper in a vessel to close the vessel. Its use is analogous to use in the context of a syringe and its plunger, and the measurement of these forces for a vessel and its closure are contemplated to be analogous to the measurement of these forces for a syringe, except that at least in most cases no liquid is ejected from a vessel when advancing the closure to a seated position.

“Slideably” means that the plunger, closure, or other removable part is permitted to slide in a syringe barrel or other vessel.

Coatings of SiO_(x) are deposited by plasma enhanced chemical vapor deposition (PECVD) or other chemical vapor deposition processes on the vessel of a pharmaceutical package, in particular a thermoplastic package, to serve as a barrier coating or layer preventing oxygen, carbon dioxide, or other gases from entering the vessel and/or to prevent leaching of the pharmaceutical material into or through the package wall. The inventors have found, however, that such barrier layers or coatings of SiO_(x) are eroded or dissolved by some fluid compositions, for example aqueous compositions having a pH above about 5. Since coatings applied by chemical vapor deposition can be very thin—tens to hundreds of nanometers thick—even a relatively slow rate of erosion can remove or reduce the effectiveness of the barrier layer in less time than the desired shelf life of a product package. This is particularly a problem for fluid pharmaceutical compositions, since many of them have a pH of roughly 7, or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical preparation, the more quickly it erodes or dissolves the SiO_(x) coating.

The inventors have further found that certain protective coatings of a saccharide do not erode quickly when exposed to fluid compositions, and in fact erode or dissolve more slowly when the fluid compositions have higher pHs within the range of 5 to 9. For example, at pH 8, the dissolution rate of a protective coating made from a saccharide is quite slow. These protective coatings can therefore be used to cover a barrier layer of SiO_(x), retaining the benefits of the barrier layer by protecting it from the fluid composition in the pharmaceutical package.

Three embodiments of the invention having many common features are those of FIGS. 7 TO 9. Some of their common features are the following, indicated in many cases by common reference characters or names. The nature of the features of each embodiment can be as described later in the specification.

The pharmaceutical packages 210 of FIGS. 7 TO 9 each include a vessel, a fluid composition, a barrier coating, and a protective coating. The vessel 250 has a lumen 212 defined at least in part by a wall 214 made of thermoplastic material.

The wall 214 has an interior surface 254 facing the lumen 212 and an outer surface 216.

The fluid composition 218 is contained in the lumen 212 and has a pH between 5 and 9.

The barrier coating 288 comprises or consists essentially of SiO_(x), wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick, the barrier coating 288 of SiO_(x) having an interior surface 220 facing the lumen 212 and an outer surface 222 facing the wall 214 interior surface 254, the barrier coating 288 being effective to reduce the ingress of atmospheric gas into the lumen 212 compared to an uncoated vessel 250. One suitable barrier composition is one where x is 2.3, for example.

The protective coating 286 is made of a saccharide. The protective coating 286 has an interior surface 224 facing the lumen 212 and an outer surface 226 facing the interior surface 220 of the barrier coating 288.

The rate of erosion of the protective coating 286, if directly contacted by the fluid composition 218, is less than the rate of erosion of the barrier coating 288, if directly contacted by the fluid composition 218.

The protective coating 286 is effective to isolate the fluid composition 218 from the barrier coating 288.

Optionally for any of the embodiments of FIGS. 7 TO 9, at least a portion of the wall 214 of the vessel 250 comprises or consists essentially of a polymer, for example a polyolefin (for example a cyclic olefin polymer, a cyclic olefin copolymer, or polypropylene), a polyester, for example polyethylene terephthalate, a polycarbonate, or any combination or copolymer of any of these. Optionally for any of the embodiments of FIGS. 7 TO 9, at least a portion of the wall 214 of the vessel 250 comprises or consists essentially of glass, for example borosilicate glass. A combination of any two or more of the materials in this paragraph can also be used.

Optionally for the embodiments of FIG. 7, the vessel 250 comprises a syringe barrel 250.

Optionally for the embodiments of FIG. 8, the vessel 250 comprises a vial that is an embodiment of the pharmaceutical package 210.

Optionally for the embodiments of FIG. 9, the vessel 250 comprises a blister package that is an embodiment of the pharmaceutical package 210287.

Optionally for any of the embodiments of FIGS. 7 TO 9, the fluid composition 218 has a pH between 5 and 6, optionally between 6 and 7, optionally between 7 and 8, optionally between 8 and 9, optionally between 6.5 and 7.5, optionally between 7.5 and 8.5, optionally between 8.5 and 9.

Optionally for any of the embodiments of FIGS. 7 TO 9, the fluid composition 218 is a liquid at 20° C. and ambient pressure at sea level, which is defined as a pressure of 760 mm Hg.

Optionally for any of the embodiments of FIGS. 7 TO 9, the fluid composition 218 is an aqueous liquid.

Optionally for any of the embodiments of FIGS. 7 TO 9, the barrier coating 288 is from 4 nm to 500 nm thick, optionally from 7 nm to 400 nm thick, optionally from 10 nm to 300 nm thick, optionally from 20 nm to 200 nm thick, optionally from 30 nm to 100 nm thick.

Optionally for any of the embodiments of FIGS. 7 TO 9, the protective coating 286 comprises or consists essentially of a saccharide.

Optionally for any of the embodiments of FIGS. 7 TO 9, the protective coating 286 as applied is between 1000 and 5000 nm thick. The thickness does not need to be uniform throughout the vessel, and will typically vary from the preferred values in portions of a vessel.

Optionally for any of the embodiments of FIGS. 7 TO 9, the rate of erosion of the protective coating 286, if directly contacted by a fluid composition 218 having a pH of 8, is less than 20%, optionally less than 15%, optionally less than 10%, optionally less than 7% , optionally from 5% to 20% , optionally 5% to 15% , optionally 5% to 10%, optionally 5% to 7%, of the rate of erosion of the barrier coating 288, if directly contacted by the same fluid composition 218 under the same conditions.

Optionally for any of the embodiments of FIGS. 7 TO 9, the protective coating 286 is at least coextensive with the barrier coating 288. The protective coating 286 alternatively can be less extensive than the barrier coating, as when the fluid composition does not contact or seldom is in contact with certain parts of the barrier coating absent the protective coating. The protective coating 286 alternatively can be more extensive than the barrier coating, as it can cover areas that are not provided with a barrier coating.

Optionally for any of the embodiments of FIGS. 7 TO 9, the pharmaceutical package 210 can have a shelf life, after the pharmaceutical package 210 is assembled, of at least one year, alternatively at least two years.

Optionally for any of the embodiments of FIGS. 7 TO 9, the shelf life is measured at 3° C., alternatively at 4° C. or higher, alternatively at 20° C. or higher, alternatively at 23° C., alternatively at 40° C.

Optionally for any of the embodiments of FIGS. 7 TO 9, the pH of the fluid composition 218 is between 5 and 6 and the thickness by TEM of the protective coating 286 is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 6 and 7 and the thickness by TEM of the protective coating 286 is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 7 and 8 and the thickness by TEM of the protective coating 286 is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 8 and 9 and the thickness by TEM of the protective coating 286 is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 5 and 6 and the thickness by TEM of the protective coating 286 is at least 150 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 6 and 7 and the thickness by TEM of the protective coating 286 is at least 150 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 7 and 8 and the thickness by TEM of the protective coating 286 is at least 150 nm at the end of the shelf life. Alternatively, the pH of the fluid composition 218 is between 8 and 9 and the thickness by TEM of the protective coating 286 is at least 150 nm at the end of the shelf life.

Optionally for any of the embodiments of FIGS. 7 TO 9, the fluid composition 218 removes the protective coating 286 at a rate of 1 nm or less of lubricity and/or protective coating thickness per 44 hours of contact with the fluid composition 218 (200 nm per year), alternatively 1 nm or less of lubricity and/or protective coating thickness per 88 hours of contact with the fluid composition 218 (100 nm per year), alternatively 1 nm or less of lubricity and/or protective coating thickness per 175 hours of contact with the fluid composition 218 (50 nm per year), alternatively 1 nm or less of lubricity and/or protective coating thickness per 250 hours of contact with the fluid composition 218 (35 nm per year), alternatively 1 nm or less of lubricity and/or protective coating thickness per 350 hours of contact with the fluid composition 218 (25 nm per year). The rate of removing the protective coating can be determined by TEM from samples exposed to the fluid composition for known periods.

Optionally for any of the embodiments of FIGS. 7 TO 9, the protective coating 286 is effective to provide a lower frictional resistance than the uncoated interior surface 254. Preferably the frictional resistance is reduced by at least 25%, more preferably by at least 45%, even more preferably by at least 60% in comparison to the uncoated interior surface 254. For example, the protective coating 286 preferably is effective to reduce the frictional resistance between a portion of the wall 214 contacted by the fluid composition 218 and a relatively sliding part 258 after the pharmaceutical package 210 is assembled. Preferably, the protective coating 286 is effective to reduce the frictional resistance between the wall 214 and a relatively sliding part 258 at least two years after the pharmaceutical package 210 is assembled.

Optionally for any of the embodiments of FIGS. 7 TO 9, the fluid composition 218 comprises a member or a combination of two or more members selected from the group consisting of:

Inhalation Anesthetics

-   Aliflurane -   Chloroform -   Cyclopropane -   Desflurane (Suprane) -   Diethyl Ether -   Enflurane (Ethrane) -   Ethyl Chloride -   Ethylene -   Halothane (Fluothane) -   Isoflurane (Forane, Isoflo) -   Isopropenyl vinyl ether -   Methoxyflurane -   methoxyflurane, -   Methoxypropane -   Nitrous Oxide -   Roflurane -   Sevoflurane (Sevorane, Ultane, Sevoflo) -   Teflurane -   Trichloroethylene -   Vinyl Ether -   Xenon     Injectable Drugs -   Ablavar (Gadofosveset Trisodium Injection) -   Abarelix Depot -   Abobotulinumtoxin A Injection (Dysport) -   ABT-263 -   ABT-869 -   ABX-EFG -   Accretropin (Somatropin Injection) -   Acetadote (Acetylcysteine Injection) -   Acetazolamide Injection (Acetazolamide Injection) -   Acetylcysteine Injection (Acetadote) -   Actemra (Tocilizumab Injection) -   Acthrel (Corticorelin Ovine Triflutate for Injection) -   Actummune -   Activase -   Acyclovir for Injection (Zovirax Injection) -   Adacel -   Adalimumab -   Adenoscan (Adenosine Injection) -   Adenosine Injection (Adenoscan) -   Adrenaclick -   AdreView (lobenguane 1123 Injection for Intravenous Use) -   Afluria -   Ak-Fluor (Fluorescein Injection) -   Aldurazyme (Laronidase) -   Alglucerase Injection (Ceredase) -   Alkeran Injection (Melphalan Hcl Injection) -   Allopurinol Sodium for Injection (Aloprim) -   Aloprim (Allopurinol Sodium for Injection) -   Alprostadil -   Alsuma (Sumatriptan Injection) -   ALTU-238 -   Amino Acid Injections -   Aminosyn -   Apidra -   Apremilast -   Alprostadil Dual Chamber System for Injection (Caverject Impulse) -   AMG 009 -   AMG 076 -   AMG 102 -   AMG 108 -   AMG 114 -   AMG 162 -   AMG 220 -   AMG 221 -   AMG 222 -   AMG 223 -   AMG 317 -   AMG 379 -   AMG 386 -   AMG 403 -   AMG 477 -   AMG 479 -   AMG 517 -   AMG 531 -   AMG 557 -   AMG 623 -   AMG 655 -   AMG 706 -   AMG 714 -   AMG 745 -   AMG 785 -   AMG 811 -   AMG 827 -   AMG 837 -   AMG 853 -   AMG 951 -   Amiodarone HCl Injection (Amiodarone HCl Injection) -   Amobarbital Sodium Injection (Amytal Sodium) -   Amytal Sodium (Amobarbital Sodium Injection) -   Anakinra -   Anti-Abeta -   Anti-Beta7 -   Anti-Beta20 -   Anti-CD4 -   Anti-CD20 -   Anti-CD40 -   Anti-IFNalpha -   Anti-IL13 -   Anti-OX40L -   Anti-oxLDS -   Anti-NGF -   Anti-NRP1 -   Arixtra -   Amphadase (Hyaluronidase Inj) -   Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection) -   Anaprox -   Anzemet Injection (Dolasetron Mesylate Injection) -   Apidra (Insulin Glulisine [rDNA origin] Inj) -   Apomab -   Aranesp (darbepoetin alfa) -   Argatroban (Argatroban Injection) -   Arginine Hydrochloride Injection (R-Gene 10 -   Aristocort -   Aristospan -   Arsenic Trioxide Injection (Trisenox) -   Articane HCl and Epinephrine Injection (Septocaine) -   Arzerra (Ofatumumab Injection) -   Asclera (Polidocanol Injection) -   Ataluren -   Ataluren-DMD -   Atenolol Inj (Tenormin I.V. Injection) -   Atracurium Besylate Injection (Atracurium Besylate Injection) -   Avastin -   Azactam Injection (Aztreonam Injection) -   Azithromycin (Zithromax Injection) -   Aztreonam Injection (Azactam Injection) -   Baclofen Injection (Lioresal Intrathecal) -   Bacteriostatic Water (Bacteriostatic Water for Injection) -   Baclofen Injection (Lioresal Intrathecal) -   Bal in Oil Ampules (Dimercarprol Injection) -   BayHepB -   BayTet -   Benadryl -   Bendamustine Hydrochloride Injection (Treanda) -   Benztropine Mesylate Injection (Cogentin) -   Betamethasone Injectable Suspension (Celestone Soluspan) -   Bexxar -   Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G     Procaine Injection) -   Blenoxane (Bleomycin Sulfate Injection) -   Bleomycin Sulfate Injection (Blenoxane) -   Boniva Injection (Ibandronate Sodium Injection) -   Botox Cosmetic (OnabotulinumtoxinA for Injection) -   BR3-FC -   Bravelle (Urofollitropin Injection) -   Bretylium (Bretylium Tosylate Injection) -   Brevital Sodium (Methohexital Sodium for Injection) -   Brethine -   Briobacept -   BTT-1023 -   Bupivacaine HCl -   Byetta -   Ca-DTPA (Pentetate Calcium Trisodium Inj) -   Cabazitaxel Injection (Jevtana) -   Caffeine Alkaloid (Caffeine and Sodium Benzoate Injection) -   Calcijex Injection (Calcitrol) -   Calcitrol (Calcijex Injection) -   Calcium Chloride (Calcium Chloride Injection 10%) -   Calcium Disodium Versenate (Edetate Calcium Disodium Injection) -   Campath (Altemtuzumab) -   Camptosar Injection (Irinotecan Hydrochloride) -   Canakinumab Injection (Ilaris) -   Capastat Sulfate (Capreomycin for Injection) -   Capreomycin for Injection (Capastat Sulfate) -   Cardiolite (Prep kit for Technetium Tc99 Sestamibi for Injection) -   Carticel -   Cathflo -   Cefazolin and Dextrose for Injection (Cefazolin Injection) -   Cefepime Hydrochloride -   Cefotaxime -   Ceftriaxone -   Cerezyme -   Carnitor Injection -   Caverject -   Celestone Soluspan -   Celsior -   Cerebyx (Fosphenytoin Sodium Injection) -   Ceredase (Alglucerase Injection) -   Ceretec (Technetium Tc99m Exametazime Injection) -   Certolizumab -   CF-101 -   Chloramphenicol Sodium Succinate (Chloramphenicol Sodium Succinate     Injection) -   Chloramphenicol Sodium Succinate Injection (Chloramphenicol Sodium     Succinate) -   Cholestagel (Colesevelam HCL) -   Choriogonadotropin Alfa Injection (Ovidrel) -   Cimzia -   Cisplatin (Cisplatin Injection) -   Clolar (Clofarabine Injection) -   Clomiphine Citrate -   Clonidine Injection (Duraclon) -   Cogentin (Benztropine Mesylate Injection) -   Colistimethate Injection (Coly-Mycin M) -   Coly-Mycin M (Colistimethate Injection) -   Compath -   Conivaptan Hcl Injection (Vaprisol) -   Conjugated Estrogens for Injection (Premarin Injection) -   Copaxone -   Corticorelin Ovine Triflutate for Injection (Acthrel) -   Corvert (Ibutilide Fumarate Injection) -   Cubicin (Daptomycin Injection) -   CF-101 -   Cyanokit (Hydroxocobalamin for Injection) -   Cytarabine Liposome Injection (DepoCyt) -   Cyanocobalamin -   Cytovene (ganciclovir) -   D.H.E. 45 -   Dacetuzumab -   Dacogen (Decitabine Injection) -   Dalteparin -   Dantrium IV (Dantrolene Sodium for Injection) -   Dantrolene Sodium for Injection (Dantrium IV) -   Daptomycin Injection (Cubicin) -   Darbepoietin Alfa -   DDAVP Injection (Desmopressin Acetate Injection) -   Decavax -   Decitabine Injection (Dacogen) -   Dehydrated Alcohol (Dehydrated Alcohol Injection) -   Denosumab Injection (Prolia) -   Delatestryl -   Delestrogen -   Delteparin Sodium -   Depacon (Valproate Sodium Injection) -   Depo Medrol (Methylprednisolone Acetate Injectable Suspension) -   DepoCyt (Cytarabine Liposome Injection) -   DepoDur (Morphine Sulfate XR Liposome Injection) -   Desmopressin Acetate Injection (DDAVP Injection) -   Depo-Estradiol -   Depo-Provera 104 mg/ml -   Depo-Provera 150 mg/ml -   Depo-Testosterone -   Dexrazoxane for Injection, Intravenous Infusion Only (Totect) -   Dextrose/Electrolytes -   Dextrose and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium     Chloride) -   Dextrose -   Diazepam Injection (Diazepam Injection) -   Digoxin Injection (Lanoxin Injection) -   Dilaudid-HP (Hydromorphone Hydrochloride Injection) -   Dimercarprol Injection (Bal in Oil Ampules) -   Diphenhydramine Injection (Benadryl Injection) -   Dipyridamole Injection (Dipyridamole Injection) -   DMOAD -   Docetaxel for Injection (Taxotere) -   Dolasetron Mesylate Injection (Anzemet Injection) -   Doribax (Doripenem for Injection) -   Doripenem for Injection (Doribax) -   Doxercalciferol Injection (Hectorol Injection) -   Doxil (Doxorubicin Hcl Liposome Injection) -   Doxorubicin Hcl Liposome Injection (Doxil) -   Duraclon (Clonidine Injection) -   Duramorph (Morphine Injection) -   Dysport (Abobotulinumtoxin A Injection) -   Ecallantide Injection (Kalbitor) -   EC-Naprosyn (naproxen) -   Edetate Calcium Disodium Injection (Calcium Disodium Versenate) -   Edex (Alprostadil for Injection) -   Engerix -   Edrophonium Injection (Enlon) -   Eliglustat Tartate -   Eloxatin (Oxaliplatin Injection) -   Emend Injection (Fosaprepitant Dimeglumine Injection) -   Enalaprilat Injection (Enalaprilat Injection) -   Enlon (Edrophonium Injection) -   Enoxaparin Sodium Injection (Lovenox) -   Eovist (Gadoxetate Disodium Injection) -   Enbrel (etanercept) -   Enoxaparin -   Epicel -   Epinepherine -   Epipen -   Epipen Jr. -   Epratuzumab -   Erbitux -   Ertapenem Injection (Invanz) -   Erythropoieten -   Essential Amino Acid Injection (Nephramine) -   Estradiol Cypionate -   Estradiol Valerate -   Etanercept -   Exenatide Injection (Byetta) -   Evlotra -   Fabrazyme (Adalsidase beta) -   Famotidine Injection -   FDG (Fludeoxyglucose F 18 Injection) -   Feraheme (Ferumoxytol Injection) -   Feridex I.V. (Ferumoxides Injectable Solution) -   Fertinex -   Ferumoxides Injectable Solution (Feridex I.V.) -   Ferumoxytol Injection (Feraheme) -   Flagyl Injection (Metronidazole Injection) -   Fluarix -   Fludara (Fludarabine Phosphate) -   Fludeoxyglucose F 18 Injection (FDG) -   Fluorescein Injection (Ak-Fluor) -   Follistim AQ Cartridge (Follitropin Beta Injection) -   Follitropin Alfa Injection (Gonal-f RFF) -   Follitropin Beta Injection (Follistim AQ Cartridge) -   Folotyn (Pralatrexate Solution for Intravenous Injection) -   Fondaparinux -   Forteo (Teriparatide (rDNA origin) Injection) -   Fostamatinib -   Fosaprepitant Dimeglumine Injection (Emend Injection) -   Foscarnet Sodium Injection (Foscavir) -   Foscavir (Foscarnet Sodium Injection) -   Fosphenytoin Sodium Injection (Cerebyx) -   Fospropofol Disodium Injection (Lusedra) -   Fragmin -   Fuzeon (enfuvirtide) -   GA101 -   Gadobenate Dimeglumine Injection (Multihance) -   Gadofosveset Trisodium Injection (Ablavar) -   Gadoteridol Injection Solution (ProHance) -   Gadoversetamide Injection (OptiMARK) -   Gadoxetate Disodium Injection (Eovist) -   Ganirelix (Ganirelix Acetate Injection) -   Gardasil -   GC1008 -   GDFD -   Gemtuzumab Ozogamicin for Injection (Mylotarg) -   Genotropin -   Gentamicin Injection -   GENZ-112638 -   Golimumab Injection (Simponi Injection) -   Gonal-f RFF (Follitropin Alfa Injection) -   Granisetron Hydrochloride (Kytril Injection) -   Gentamicin Sulfate -   Glatiramer Acetate -   Glucagen -   Glucagon -   HAE1 -   Haldol (Haloperidol Injection) -   Havrix -   Hectorol Injection (Doxercalciferol Injection) -   Hedgehog Pathway Inhibitor -   Heparin -   Herceptin -   hG-CSF -   Humalog -   Human Growth Hormone -   Humatrope -   HuMax -   Humegon -   Humira -   Humulin -   Ibandronate Sodium Injection (Boniva Injection) -   Ibuprofen Lysine Injection (NeoProfen) -   Ibutilide Fumarate Injection (Corvert) -   Idamycin PFS (Idarubicin Hydrochloride Injection) -   Idarubicin Hydrochloride Injection (Idamycin PFS) -   Ilaris (Canakinumab Injection) -   Imipenem and Cilastatin for Injection (Primaxin I.V.) -   Imitrex -   Incobotulinumtoxin A for Injection (Xeomin) -   Increlex (Mecasermin [rDNA origin] Injection) -   Indocin IV (Indomethacin Inj) -   Indomethacin Inj (Indocin IV) -   Infanrix -   Innohep -   Insulin -   Insulin Aspart [rDNA origin] Inj (NovoLog) -   Insulin Glargine [rDNA origin] Injection (Lantus) -   Insulin Glulisine [rDNA origin] Inj (Apidra) -   Interferon alfa-2b, Recombinant for Injection (Intron A) -   Intron A (Interferon alfa-2b, Recombinant for Injection) -   Invanz (Ertapenem Injection) -   Invega Sustenna (Paliperidone Palmitate Extended-Release Injectable     Suspension) -   Invirase (saquinavir mesylate) -   Iobenguane 1123 Injection for Intravenous Use (AdreView) -   Iopromide Injection (Ultravist) -   Ioversol Injection (Optiray Injection) -   Iplex (Mecasermin Rinfabate [rDNA origin] Injection) -   Iprivask -   Irinotecan Hydrochloride (Camptosar Injection) -   Iron Sucrose Injection (Venofer) -   Istodax (Romidepsin for Injection) -   Itraconazole Injection (Sporanox Injection) -   Jevtana (Cabazitaxel Injection) -   Jonexa -   Kalbitor (Ecallantide Injection) -   KCL in D5NS (Potassium Chloride in 5% Dextrose and Sodium Chloride     Injection) -   KCL in D5W -   KCL in NS -   Kenalog 10 Injection (Triamcinolone Acetonide Injectable Suspension) -   Kepivance (Palifermin) -   Keppra Injection (Levetiracetam) -   Keratinocyte -   KFG -   Kinase Inhibitor -   Kineret (Anakinra) -   Kinlytic (Urokinase Injection) -   Kinrix -   Klonopin (clonazepam) -   Kytril Injection (Granisetron Hydrochloride) -   lacosamide Tablet and Injection (Vimpat) -   Lactated Ringer's -   Lanoxin Injection (Digoxin Injection) -   Lansoprazole for Injection (Prevacid I.V.) -   Lantus -   Leucovorin Calcium (Leucovorin Calcium Injection) -   Lente (L) -   Leptin -   Levemir -   Leukine Sargramostim -   Leuprolide Acetate -   Levothyroxine -   Levetiracetam (Keppra Injection) -   Lovenox -   Levocarnitine Injection (Carnitor Injection) -   Lexiscan (Regadenoson Injection) -   Lioresal Intrathecal (Baclofen Injection) -   Liraglutide [rDNA] Injection (Victoza) -   Lovenox (Enoxaparin Sodium Injection) -   Lucentis (Ranibizumab Injection) -   Lumizyme -   Lupron (Leuprolide Acetate Injection) -   Lusedra (Fospropofol Disodium Injection) -   Maci -   Magnesium Sulfate (Magnesium Sulfate Injection) -   Mannitol Injection (Mannitol IV) -   Marcaine (Bupivacaine Hydrochloride and Epinephrine Injection) -   Maxipime (Cefepime Hydrochloride for Injection) -   MDP Multidose Kit of Technetium Injection (Technetium Tc99m     Medronate Injection) -   Mecasermin [rDNA origin] Injection (Increlex) -   Mecasermin Rinfabate [rDNA origin] Injection (Iplex) -   Melphalan Hcl Injection (Alkeran Injection) -   Methotrexate -   Menactra -   Menopur (Menotropins Injection) -   Menotropins for Injection (Repronex) -   Methohexital Sodium for Injection (Brevital Sodium) -   Methyldopate Hydrochloride Injection, Solution (Methyldopate Hcl) -   Methylene Blue (Methylene Blue Injection) -   Methylprednisolone Acetate Injectable Suspension (Depo Medrol) -   MetMab -   Metoclopramide Injection (Reglan Injection) -   Metrodin (Urofollitropin for Injection) -   Metronidazole Injection (Flagyl Injection) -   Miacalcin -   Midazolam (Midazolam Injection) -   Mimpara (Cinacalet) -   Minocin Injection (Minocycline Inj) -   Minocycline Inj (Minocin Injection) -   Mipomersen -   Mitoxantrone for Injection Concentrate (Novantrone) -   Morphine Injection (Duramorph) -   Morphine Sulfate XR Liposome Injection (DepoDur) -   Morrhuate Sodium (Morrhuate Sodium Injection) -   Motesanib -   Mozobil (Plerixafor Injection) -   Multihance (Gadobenate Dimeglumine Injection) -   Multiple Electrolytes and Dextrose Injection -   Multiple Electrolytes Injection -   Mylotarg (Gemtuzumab Ozogamicin for Injection) -   Myozyme (Alglucosidase alfa) -   Nafcillin Injection (Nafcillin Sodium) -   Nafcillin Sodium (Nafcillin Injection) -   Naltrexone XR Inj (Vivitrol) -   Naprosyn (naproxen) -   NeoProfen (Ibuprofen Lysine Injection) -   Nandrol Decanoate -   Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection) -   NEO-GAA -   NeoTect (Technetium Tc 99m Depreotide Injection) -   Nephramine (Essential Amino Acid Injection) -   Neulasta (pegfilgrastim) -   Neupogen (Filgrastim) -   Novolin -   Novolog -   NeoRecormon -   Neutrexin (Trimetrexate Glucuronate Inj) -   NPH (N) -   Nexterone (Amiodarone HCl Injection) -   Norditropin (Somatropin Injection) -   Normal Saline (Sodium Chloride Injection) -   Novantrone (Mitoxantrone for Injection Concentrate) -   Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane Suspension     and 30% Regular, Human Insulin Injection) -   NovoLog (Insulin Aspart [rDNA origin] Inj) -   Nplate (romiplostim) -   Nutropin (Somatropin (rDNA origin) for Inj) -   Nutropin AQ -   Nutropin Depot (Somatropin (rDNA origin) for Inj) -   Octreotide Acetate Injection (Sandostatin LAR) -   Ocrelizumab -   Ofatumumab Injection (Arzerra) -   Olanzapine Extended Release Injectable Suspension (Zyprexa Relprevv) -   Omnitarg -   Omnitrope (Somatropin [ rDNA origin] Injection) -   Ondansetron Hydrochloride Injection (Zofran Injection) -   OptiMARK (Gadoversetamide Injection) -   Optiray Injection (Ioversol Injection) -   Orencia -   Osmitrol Injection in Aviva (Mannitol Injection in Aviva Plastic     Vessel 250) -   Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex Plastic     Vessel 250) -   Osteoprotegrin -   Ovidrel (Choriogonadotropin Alfa Injection) -   Oxacillin (Oxacillin for Injection) -   Oxaliplatin Injection (Eloxatin) -   Oxytocin Injection (Pitocin) -   Paliperidone Palmitate Extended-Release Injectable Suspension     (Invega Sustenna) -   Pamidronate Disodium Injection (Pamidronate Disodium Injection) -   Panitumumab Injection for Intravenous Use (Vectibix) -   Papaverine Hydrochloride Injection (Papaverine Injection) -   Papaverine Injection (Papaverine Hydrochloride Injection) -   Parathyroid Hormone -   Paricalcitol Injection Fliptop Vial (Zemplar Injection) -   PARP Inhibitor -   Pediarix -   PEGlntron -   Peginterferon -   Pegfilgrastim -   Penicillin G Benzathine and Penicillin G Procaine -   Pentetate Calcium Trisodium Inj (Ca-DTPA) -   Pentetate Zinc Trisodium Injection (Zn-DTPA) -   Pepcid Injection (Famotidine Injection) -   Pergonal -   Pertuzumab -   Phentolamine Mesylate (Phentolamine Mesylate for Injection) -   Physostigmine Salicylate (Physostigmine Salicylate (injection)) -   Physostigmine Salicylate (injection) (Physostigmine Salicylate) -   Piperacillin and Tazobactam Injection (Zosyn) -   Pitocin (Oxytocin Injection) -   Plasma-Lyte 148 (Multiple Electrolytes Inj) -   Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and Dextrose     Injection in Viaflex -   Plastic Vessel 250) -   PlasmaLyte -   Plerixafor Injection (Mozobil) -   Polidocanol Injection (Asclera) -   Potassium Chloride -   Pralatrexate Solution for Intravenous Injection (Folotyn) -   Pramlintide Acetate Injection (Symlin) -   Premarin Injection (Conjugated Estrogens for Injection) -   Prep kit for Technetium Tc99 Sestamibi for Injection (Cardiolite) -   Prevacid I.V. (Lansoprazole for Injection) -   Primaxin I.V. (Imipenem and Cilastatin for Injection) -   Prochymal -   Procrit -   Progesterone -   ProHance (Gadoteridol Injection Solution) -   Prolia (Denosumab Injection) -   Promethazine HCl Injection (Promethazine Hydrochloride Injection) -   Propranolol Hydrochloride Injection (Propranolol Hydrochloride     Injection) -   Quinidine Gluconate Injection (Quinidine Injection) -   Quinidine Injection (Quinidine Gluconate Injection) -   R-Gene 10 (Arginine Hydrochloride Injection) -   Ranibizumab Injection (Lucentis) -   Ranitidine Hydrochloride Injection (Zantac Injection) -   Raptiva -   Reclast (Zoledronic Acid Injection) -   Recombivarix HB -   Regadenoson Injection (Lexiscan) -   Reglan Injection (Metoclopramide Injection) -   Remicade -   Renagel -   Renvela (Sevelamer Carbonate) -   Repronex (Menotropins for Injection) -   Retrovir IV (Zidovudine Injection) -   rhApo2L/TRAIL -   Ringer's and 5% Dextrose Injection (Ringers in Dextrose) -   Ringer's Injection (Ringers Injection) -   Rituxan -   Rituximab -   Rocephin (ceftriaxone) -   Rocuronium Bromide Injection (Zemuron) -   Roferon-A (interferon alfa-2a) -   Romazicon (flumazenil) -   Romidepsin for Injection (Istodax) -   Saizen (Somatropin Injection) -   Sandostatin LAR (Octreotide Acetate Injection) -   Sclerostin Ab -   Sensipar (cinacalcet) -   Sensorcaine (Bupivacaine HCl Injections) -   Septocaine (Articane HCl and Epinephrine Injection) -   Serostim LQ (Somatropin (rDNA origin) Injection) -   Simponi Injection (Golimumab Injection) -   Sodium Acetate (Sodium Acetate Injection) -   Sodium Bicarbonate (Sodium Bicarbonate 5% Injection) -   Sodium Lactate (Sodium Lactate Injection in AVIVA) -   Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul) -   Somatropin (rDNA origin) for Inj (Nutropin) -   Sporanox Injection (Itraconazole Injection) -   Stelara Injection (Ustekinumab) -   Stemgen -   Sufenta (Sufentanil Citrate Injection) -   Sufentanil Citrate Injection (Sufenta) -   Sumavel -   Sumatriptan Injection (Alsuma) -   Symlin -   Symlin Pen -   Systemic Hedgehog Antagonist -   Synvisc-One (Hylan G-F 20 Single Intra-articular Injection) -   Tarceva -   Taxotere (Docetaxel for Injection) -   Technetium Tc 99m -   Telavancin for Injection (Vibativ) -   Temsirolimus Injection (Torisel) -   Tenormin I.V. Injection (Atenolol Inj) -   Teriparatide (rDNA origin) Injection (Forteo) -   Testosterone Cypionate -   Testosterone Enanthate -   Testosterone Propionate -   Tev-Tropin (Somatropin, rDNA Origin, for Injection) -   tgAAC94 -   Thallous Chloride -   Theophylline -   Thiotepa (Thiotepa Injection) -   Thymoglobulin (Anti-Thymocyte Globulin (Rabbit) -   Thyrogen (Thyrotropin Alfa for Injection) -   Ticarcillin Disodium and Clavulanate Potassium Galaxy (Timentin     Injection) -   Tigan Injection (Trimethobenzamide Hydrochloride Injectable) -   Timentin Injection (Ticarcillin Disodium and Clavulanate Potassium     Galaxy) -   TNKase -   Tobramycin Injection (Tobramycin Injection) -   Tocilizumab Injection (Actemra) -   Torisel (Temsirolimus Injection) -   Totect (Dexrazoxane for Injection, Intravenous Infusion Only) -   Trastuzumab-DM1 -   Travasol (Amino Acids (Injection)) -   Treanda (Bendamustine Hydrochloride Injection) -   Trelstar (Triptorelin Pamoate for Injectable Suspension) -   Triamcinolone Acetonide -   Triamcinolone Diacetate -   Triamcinolone Hexacetonide Injectable Suspension (Aristospan     Injection 20 mg) -   Triesence (Triamcinolone Acetonide Injectable Suspension) -   Trimethobenzamide Hydrochloride Injectable (Tigan Injection) -   Trimetrexate Glucuronate Inj (Neutrexin) -   Triptorelin Pamoate for Injectable Suspension (Trelstar) -   Twinject -   Trivaris (Triamcinolone Acetonide Injectable Suspension) -   Trisenox (Arsenic Trioxide Injection) -   Twinrix -   Typhoid Vi -   Ultravist (Iopromide Injection) -   Urofollitropin for Injection (Metrodin) -   Urokinase Injection (Kinlytic) -   Ustekinumab (Stelara Injection) -   Ultralente (U) -   Valium (diazepam) -   Valproate Sodium Injection (Depacon) -   Valtropin (Somatropin Injection) -   Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection) -   Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride) -   Vaprisol (Conivaptan Hcl Injection) -   VAQTA -   Vasovist (Gadofosveset Trisodium Injection for Intravenous Use) -   Vectibix (Panitumumab Injection for Intravenous Use) -   Venofer (Iron Sucrose Injection) -   Verteporfin Inj (Visudyne) -   Vibativ (Telavancin for Injection) -   Victoza (Liraglutide [rDNA] Injection) -   Vimpat (lacosamide Tablet and Injection) -   Vinblastine Sulfate (Vinblastine Sulfate Injection) -   Vincasar PFS (Vincristine Sulfate Injection) -   Victoza -   Vincristine Sulfate (Vincristine Sulfate Injection) -   Visudyne (Verteporfin Inj) -   Vitamin B-12 -   Vivitrol (Naltrexone XR Inj) -   Voluven (Hydroxyethyl Starch in Sodium Chloride Injection) -   Xeloda -   Xenical (orlistat) -   Xeomin (Incobotulinumtoxin A for Injection) -   Xolair -   Zantac Injection (Ranitidine Hydrochloride Injection) -   Zemplar Injection (Paricalcitol Injection Fliptop Vial) -   Zemuron (Rocuronium Bromide Injection) -   Zenapax (daclizumab) -   Zevalin -   Zidovudine Injection (Retrovir IV) -   Zithromax Injection (Azithromycin) -   Zn-DTPA (Pentetate Zinc Trisodium Injection) -   Zofran Injection (Ondansetron Hydrochloride Injection) -   Zingo -   Zoledronic Acid for Inj (Zometa) -   Zoledronic Acid Injection (Reclast) -   Zometa (Zoledronic Acid for Inj) -   Zosyn (Piperacillin and Tazobactam Injection) -   Zyprexa Relprevv (Olanzapine Extended Release Injectable Suspension)     Liquid Drugs (Non-Injectable) -   Abilify -   AccuNeb (Albuterol Sulfate Inhalation Solution) -   Actidose Aqua (Activated Charcoal Suspension) -   Activated Charcoal Suspension (Actidose Aqua) -   Advair -   Agenerase Oral Solution (Amprenavir Oral Solution) -   Akten (Lidocaine Hydrochloride Ophthalmic Gel) -   Alamast (Pemirolast Potassium Ophthalmic Solution) -   Albumin (Human) 5% Solution (Buminate 5%) -   Albuterol Sulfate Inhalation Solution -   Alinia -   Alocril -   Alphagan -   Alrex -   Alvesco -   Amprenavir Oral Solution -   Analpram-HC -   Arformoterol Tartrate Inhalation Solution (Brovana) -   Aristospan Injection 20 mg (Triamcinolone Hexacetonide Injectable     Suspension) -   Asacol -   Asmanex -   Astepro -   Astepro (Azelastine Hydrochloride Nasal Spray) -   Atrovent Nasal Spray (Ipratropium Bromide Nasal Spray) -   Atrovent Nasal Spray 0.06 -   Augmentin ES-600 -   Azasite (Azithromycin Ophthalmic Solution) -   Azelaic Acid (Finacea Gel) -   Azelastine Hydrochloride Nasal Spray (Astepro) -   Azelex (Azelaic Acid Cream) -   Azopt (Brinzolamide Ophthalmic Suspension) -   Bacteriostatic Saline -   Balanced Salt -   Bepotastine -   Bactroban Nasal -   Bactroban -   Beclovent -   Benzac W -   Betimol -   Betoptic S -   Bepreve -   Bimatoprost Ophthalmic Solution -   Bleph 10 (Sulfacetamide Sodium Ophthalmic Solution 10%) -   Brinzolamide Ophthalmic Suspension (Azopt) -   Bromfenac Ophthalmic Solution (Xibrom) -   Bromhist -   Brovana (Arformoterol Tartrate Inhalation Solution) -   Budesonide Inhalation Suspension (Pulmicort Respules) -   Cambia (Diclofenac Potassium for Oral Solution) -   Capex -   Carac -   Carboxine-PSE -   Carnitor -   Cayston (Aztreonam for Inhalation Solution) -   Cellcept -   Centany -   Cerumenex -   Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic Solution) -   Ciprodex -   Ciprofloxacin HCL Ophthalmic Solution (Ciloxan Ophthalmic Solution) -   Clemastine Fumarate Syrup (Clemastine Fumarate Syrup) -   CoLyte (PEG Electrolytes Solution) -   Combiven -   Comtan -   Condylox -   Cordran -   Cortisporin Ophthalmic Suspension -   Cortisporin Otic Suspension -   Cromolyn Sodium Inhalation Solution (Intal Nebulizer Solution) -   Cromolyn Sodium Ophthalmic Solution (Opticrom) -   Crystalline Amino Acid Solution with Electrolytes (Aminosyn     Electrolytes) -   Cutivate -   Cuvposa (Glycopyrrolate Oral Solution) -   Cyanocobalamin (CaloMist Nasal Spray) -   Cyclosporine Oral Solution (Gengraf Oral Solution) -   Cyclogyl -   Cysview (Hexaminolevulinate Hydrochloride Intravesical Solution) -   DermOtic Oil (Fluocinolone Acetonide Oil Ear Drops) -   Desmopressin Acetate Nasal Spray -   DDAVP -   Derma-Smoothe/FS -   Dexamethasone Intensol -   Dianeal Low Calcium -   Dianeal PD -   Diclofenac Potassium for Oral Solution (Cambia) -   Didanosine Pediatric Powder for Oral Solution (Videx) -   Differin -   Dilantin 125 (Phenytoin Oral Suspension) -   Ditropan -   Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt) -   Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution     (Cosopt) -   Dovonex Scalp (Calcipotriene Solution) -   Doxycycline Calcium Oral Suspension (Vibramycin Oral) -   Efudex -   Elaprase (Idursulfase Solution) -   Elestat (Epinastine HCl Ophthalmic Solution) -   Elocon -   Epinastine HCl Ophthalmic Solution (Elestat) -   Epivir HBV -   Epogen (Epoetin alfa) -   Erythromycin Topical Solution 1.5% (Staticin) -   Ethiodol (Ethiodized Oil) -   Ethosuximide Oral Solution (Zarontin Oral Solution) -   Eurax -   Extraneal (Icodextrin Peritoneal Dialysis Solution) -   Felbatol -   Feridex I.V. (Ferumoxides Injectable Solution) -   Flovent -   Floxin Otic (Ofloxacin Otic Solution) -   Flo-Pred (Prednisolone Acetate Oral Suspension) -   Fluoroplex -   Flunisolide Nasal Solution (Flunisolide Nasal Spray 0.025%) -   Fluorometholone Ophthalmic Suspension (FML) -   Flurbiprofen Sodium Ophthalmic Solution (Ocufen) -   FML -   Foradil -   Formoterol Fumarate Inhalation Solution (Perforomist) -   Fosamax -   Furadantin (Nitrofurantoin Oral Suspension) -   Furoxone -   Gammagard Liquid (Immune Globulin Intravenous (Human) 10%) -   Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension) -   Gatifloxacin Ophthalmic Solution (Zymar) -   Gengraf Oral Solution (Cyclosporine Oral Solution) -   Glycopyrrolate Oral Solution (Cuvposa) -   Halcinonide Topical Solution (Halog Solution) -   Halog Solution (Halcinonide Topical Solution) -   HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution) -   Heparin Lock Flush Solution (Hepflush 10 -   Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview) -   Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab     Elixir) -   Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution) -   IAP Antagonist -   Isopto -   Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray) -   Itraconazole Oral Solution (Sporanox Oral Solution) -   Ketorolac Tromethamine Ophthalmic Solution (Acular LS) -   Kaletra -   Lanoxin -   Lexiva -   Leuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg) -   Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon) -   Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor) -   Levofloxacin Ophthalmic Solution 0.5% (Quixin) -   Lidocaine HCl Sterile Solution (Xylocaine MPF Sterile Solution) -   Lok Pak (Heparin Lock Flush Solution) -   Lorazepam Intensol -   Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen Oral     Solution) -   Lotemax (Loteprednol Etabonate Ophthalmic Suspension) -   Loteprednol Etabonate Ophthalmic Suspension (Alrex) -   Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium) -   Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma) -   Lupron Depot 11.25 mg (Leuprolide Acetate for Depot Suspension) -   Megestrol Acetate Oral Suspension (Megestrol Acetate Oral     Suspension) -   MEK Inhibitor -   Mepron -   Mesnex -   Mestinon -   Mesalamine Rectal Suspension Enema (Rowasa) -   Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution) -   MetMab -   Methyldopate Hcl (Methyldopate Hydrochloride Injection, Solution) -   Methylin Oral Solution (Methylphenidate HCl Oral Solution 5 mg/5 mL     and 10 mg/5 mL) -   Methylprednisolone Acetate Injectable Suspension (Depo Medrol) -   Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL (Methylin     Oral Solution) -   Methylprednisolone sodium succinate (Solu Medrol) -   Metipranolol Ophthalmic Solution (Optipranolol) -   Migranal -   Miochol-E (Acetylcholine Chloride Intraocular Solution) -   Micro-K for Liquid Suspension (Potassium Chloride Extended Release     Formulation for Liquid Suspension) -   Minocin (Minocycline Hydrochloride Oral Suspension) -   Nasacort -   Neomycin and Polymyxin B Sulfates and Hydrocortisone -   Nepafenac Ophthalmic Suspension (Nevanac) -   Nevanac (Nepafenac Ophthalmic Suspension) -   Nitrofurantoin Oral Suspension (Furadantin) -   Noxafil (Posaconazole Oral Suspension) -   Nystatin (oral) (Nystatin Oral Suspension) -   Nystatin Oral Suspension (Nystatin (oral)) -   Ocufen (Flurbiprofen Sodium Ophthalmic Solution) -   Ofloxacin Ophthalmic Solution (Ofloxacin Ophthalmic Solution) -   Ofloxacin Otic Solution (Floxin Otic) -   Olopatadine Hydrochloride Ophthalmic Solution (Pataday) -   Opticrom (Cromolyn Sodium Ophthalmic Solution) -   Optipranolol (Metipranolol Ophthalmic Solution) -   Patanol -   Pediapred -   PerioGard -   Phenytoin Oral Suspension (Dilantin 125) -   Phisohex -   Posaconazole Oral Suspension (Noxafil) -   Potassium Chloride Extended Release Formulation for Liquid     Suspension (Micro-K for Liquid Suspension) -   Pataday (Olopatadine Hydrochloride Ophthalmic Solution) -   Patanase Nasal Spray (Olopatadine Hydrochloride Nasal Spray) -   PEG Electrolytes Solution (CoLyte) -   Pemirolast Potassium Ophthalmic Solution (Alamast) -   Penlac (Ciclopirox Topical Solution) -   PENNSAID (Diclofenac Sodium Topical Solution) -   Perforomist (Formoterol Fumarate Inhalation Solution) -   Peritoneal Dialysis Solution -   Phenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine) -   Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution) -   Podofilox (Podofilox Topical Solution) -   Pred Forte (Prednisolone Acetate Ophthalmic Suspension) -   Pralatrexate Solution for Intravenous Injection (Folotyn) -   Pred Mild -   Prednisone Intensol -   Prednisolone Acetate Ophthalmic Suspension (Pred Forte) -   Prevacid -   PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration     Solution) -   ProAir -   Proglycem -   ProHance (Gadoteridol Injection Solution) -   Proparacaine Hydrochloride Ophthalmic Solution (Alcaine) -   Propine -   Pulmicort -   Pulmozyme -   Quixin (Levofloxacin Ophthalmic Solution 0.5%) -   QVAR -   Rapamune -   Rebetol -   Relacon-HC -   Rotarix (Rotavirus Vaccine, Live, Oral Suspension) -   Rotavirus Vaccine, Live, Oral Suspension (Rotarix) -   Rowasa (Mesalamine Rectal Suspension Enema) -   Sabril (Vigabatrin Oral Solution) -   Sacrosidase Oral Solution (Sucraid) -   Sandimmune -   Sepra -   Serevent Diskus -   Solu Cortef (Hydrocortisone Sodium Succinate) -   Solu Medrol (Methylprednisolone sodium succinate) -   Spiriva -   Sporanox Oral Solution (Itraconazole Oral Solution) -   Staticin (Erythromycin Topical Solution 1.5%) -   Stalevo -   Starlix -   Sterile Hemofiltration Hemodiafiltration Solution (PrismaSol     Solution) -   Stimate -   Sucralfate (Carafate Suspension) -   Sulfacetamide Sodium Ophthalmic Solution 10% (Bleph 10 -   Synarel Nasal Solution (Nafarelin Acetate Nasal Solution for     Endometriosis) -   Taclonex Scalp (Calcipotriene and Betamethasone Dipropionate Topical     Suspension) -   Tamiflu -   Tobi -   TobraDex -   Tobradex ST (Tobramycin/Dexamethasone Ophthalmic Suspension     0.3%/0.05%) -   Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex     ST) -   Timolol -   Timoptic -   Travatan Z -   Treprostinil Inhalation Solution (Tyvaso) -   Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution) -   Tyvaso (Treprostinil Inhalation Solution) -   Ventolin -   Vfend -   Vibramycin Oral (Doxycycline Calcium Oral Suspension) -   Videx (Didanosine Pediatric Powder for Oral Solution) -   Vigabatrin Oral Solution (Sabril) -   Viokase -   Viracept -   Viramune -   Vitamin K1 (Fluid Colloidal Solution of Vitamin K1) -   Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution) -   Zarontin Oral Solution (Ethosuximide Oral Solution) -   Ziagen -   Zyvox -   Zymar (Gatifloxacin Ophthalmic Solution) -   Zymaxid (Gatifloxacin Ophthalmic Solution)     Drug Classes -   5-alpha-reductase inhibitors -   5-aminosalicylates -   5HT3 receptor antagonists -   adamantane antivirals -   adrenal cortical steroids -   adrenal corticosteroid inhibitors -   adrenergic bronchodilators -   agents for hypertensive emergencies -   agents for pulmonary hypertension -   aldosterone receptor antagonists -   alkylating agents -   alpha-adrenoreceptor antagonists -   alpha-glucosidase inhibitors -   alternative medicines -   amebicides -   aminoglycosides -   aminopenicillins -   aminosalicylates -   amylin analogs -   Analgesic Combinations -   Analgesics -   androgens and anabolic steroids -   angiotensin converting enzyme inhibitors -   angiotensin II inhibitors -   anorectal preparations -   anorexiants -   antacids -   anthelmintics -   anti-angiogenic ophthalmic agents -   anti-CTLA-4 monoclonal antibodies -   anti-infectives -   antiadrenergic agents, centrally acting -   antiadrenergic agents, peripherally acting -   antiandrogens -   antianginal agents -   antiarrhythmic agents -   antiasthmatic combinations -   antibiotics/antineoplastics -   anticholinergic antiemetics -   anticholinergic antiparkinson agents -   anticholinergic bronchodilators -   anticholinergic chronotropic agents -   anticholinergics/antispasmodics -   anticoagulants -   anticonvulsants -   antidepressants -   antidiabetic agents -   antidiabetic combinations -   antidiarrheals -   antidiuretic hormones -   antidotes -   antiemetic/antivertigo agents -   antifungals -   antigonadotropic agents -   antigout agents -   antihistamines -   antihyperlipidemic agents -   antihyperlipidemic combinations -   antihypertensive combinations -   antihyperuricemic agents -   antimalarial agents -   antimalarial combinations -   antimalarial quinolines -   antimetabolites -   antimigraine agents -   antineoplastic detoxifying agents -   antineoplastic interferons -   antineoplastic monoclonal antibodies -   antineoplastics -   antiparkinson agents -   antiplatelet agents -   antipseudomonal penicillins -   antipsoriatics -   antipsychotics -   antirheumatics -   antiseptic and germicides -   antithyroid agents -   antitoxins and antivenins -   antituberculosis agents -   antituberculosis combinations -   antitussives -   antiviral agents -   antiviral combinations -   antiviral interferons -   anxiolytics, sedatives, and hypnotics -   aromatase inhibitors -   atypical antipsychotics -   azole antifungals -   bacterial vaccines -   barbiturate anticonvulsants -   barbiturates -   BCR-ABL tyrosine kinase inhibitors -   benzodiazepine anticonvulsants -   benzodiazepines -   beta-adrenergic blocking agents -   beta-lactamase inhibitors -   bile acid sequestrants -   biologicals -   bisphosphonates -   bone resorption inhibitors -   bronchodilator combinations -   bronchodilators -   calcitonin -   calcium channel blocking agents -   carbamate anticonvulsants -   carbapenems -   carbonic anhydrase inhibitor anticonvulsants -   carbonic anhydrase inhibitors -   cardiac stressing agents -   cardioselective beta blockers -   cardiovascular agents -   catecholamines -   CD20 monoclonal antibodies -   CD33 monoclonal antibodies -   CD52 monoclonal antibodies -   central nervous system agents -   cephalosporins -   cerumenolytics -   chelating agents -   chemokine receptor antagonist -   chloride channel activators -   cholesterol absorption inhibitors -   cholinergic agonists -   cholinergic muscle stimulants -   cholinesterase inhibitors -   CNS stimulants -   coagulation modifiers -   colony stimulating factors -   contraceptives -   corticotropin -   coumarins and indandiones -   cox-2 inhibitors -   decongestants -   dermatological agents -   diagnostic radiopharmaceuticals -   dibenzazepine anticonvulsants -   digestive enzymes -   dipeptidyl peptidase 4 inhibitors -   diuretics -   dopaminergic antiparkinsonism agents -   drugs used in alcohol dependence -   echinocandins -   EGFR inhibitors -   estrogen receptor antagonists -   estrogens -   expectorants -   factor Xa inhibitors -   fatty acid derivative anticonvulsants -   fibric acid derivatives -   first generation cephalosporins -   fourth generation cephalosporins -   functional bowel disorder agents -   gallstone solubilizing agents -   gamma-aminobutyric acid analogs -   gamma-aminobutyric acid reuptake inhibitors -   gamma-aminobutyric acid transaminase inhibitors -   gastrointestinal agents -   general anesthetics -   genitourinary tract agents -   GI stimulants -   glucocorticoids -   glucose elevating agents -   glycopeptide antibiotics -   glycoprotein platelet inhibitors -   glycylcyclines -   gonadotropin releasing hormones -   gonadotropin-releasing hormone antagonists -   gonadotropins -   group I antiarrhythmics -   group II antiarrhythmics -   group III antiarrhythmics -   group IV antiarrhythmics -   group V antiarrhythmics -   growth hormone receptor blockers -   growth hormones -   H. pylori eradication agents -   H2 antagonists -   hematopoietic stem cell mobilizer -   heparin antagonists -   heparins -   HER2 inhibitors -   herbal products -   histone deacetylase inhibitors -   hormone replacement therapy -   hormones -   hormones/antineoplastics -   hydantoin anticonvulsants -   illicit (street) drugs -   immune globulins -   immunologic agents -   immunosuppressive agents -   impotence agents -   in vivo diagnostic biologicals -   incretin mimetics -   inhaled anti-infectives -   inhaled corticosteroids -   inotropic agents -   insulin -   insulin-like growth factor -   integrase strand transfer inhibitor -   interferons -   intravenous nutritional products -   iodinated contrast media -   ionic iodinated contrast media -   iron products -   ketolides -   laxatives -   leprostatics -   leukotriene modifiers -   lincomycin derivatives -   lipoglycopeptides -   local injectable anesthetics -   loop diuretics -   lung surfactants -   lymphatic staining agents -   lysosomal enzymes -   macrolide derivatives -   macrolides -   magnetic resonance imaging contrast media -   mast cell stabilizers -   medical gas -   meglitinides -   metabolic agents -   methylxanthines -   mineralocorticoids -   minerals and electrolytes -   miscellaneous agents -   miscellaneous analgesics -   miscellaneous antibiotics -   miscellaneous anticonvulsants -   miscellaneous antidepressants -   miscellaneous antidiabetic agents -   miscellaneous antiemetics -   miscellaneous antifungals -   miscellaneous antihyperlipidemic agents -   miscellaneous antimalarials -   miscellaneous antineoplastics -   miscellaneous antiparkinson agents -   miscellaneous antipsychotic agents -   miscellaneous antituberculosis agents -   miscellaneous antivirals -   miscellaneous anxiolytics, sedatives and hypnotics -   miscellaneous biologicals -   miscellaneous bone resorption inhibitors -   miscellaneous cardiovascular agents -   miscellaneous central nervous system agents -   miscellaneous coagulation modifiers -   miscellaneous diuretics -   miscellaneous genitourinary tract agents -   miscellaneous GI agents -   miscellaneous hormones -   miscellaneous metabolic agents -   miscellaneous ophthalmic agents -   miscellaneous otic agents -   miscellaneous respiratory agents -   miscellaneous sex hormones -   miscellaneous topical agents -   miscellaneous uncategorized agents -   miscellaneous vaginal agents -   mitotic inhibitors -   monoamine oxidase inhibitors -   monoclonal antibodies -   mouth and throat products -   mTOR inhibitors -   mTOR kinase inhibitors -   mucolytics -   multikinase inhibitors -   muscle relaxants -   mydriatics -   narcotic analgesic combinations -   narcotic analgesics -   nasal anti-infectives -   nasal antihistamines and decongestants -   nasal lubricants and irrigations -   nasal preparations -   nasal steroids -   natural penicillins -   neuraminidase inhibitors -   neuromuscular blocking agents -   next generation cephalosporins -   nicotinic acid derivatives -   nitrates -   NNRTIs -   non-cardioselective beta blockers -   non-iodinated contrast media -   non-ionic iodinated contrast media -   non-sulfonylureas -   nonsteroidal anti-inflammatory agents -   norepinephrine reuptake inhibitors -   norepinephrine-dopamine reuptake inhibitors -   nucleoside reverse transcriptase inhibitors (NRTIs) -   nutraceutical products -   nutritional products -   ophthalmic anesthetics -   ophthalmic anti-infectives -   ophthalmic anti-inflammatory agents -   ophthalmic antihistamines and decongestants -   ophthalmic diagnostic agents -   ophthalmic glaucoma agents -   ophthalmic lubricants and irrigations -   ophthalmic preparations -   ophthalmic steroids -   ophthalmic steroids with anti-infectives -   ophthalmic surgical agents -   oral nutritional supplements -   otic anesthetics -   otic anti-infectives -   otic preparations -   otic steroids -   otic steroids with anti-infectives -   oxazolidinedione anticonvulsants -   parathyroid hormone and analogs -   penicillinase resistant penicillins -   penicillins -   peripheral opioid receptor antagonists -   peripheral vasodilators -   peripherally acting antiobesity agents -   phenothiazine antiemetics -   phenothiazine antipsychotics -   phenylpiperazine antidepressants -   plasma expanders -   platelet aggregation inhibitors -   platelet-stimulating agents -   polyenes -   potassium-sparing diuretics -   probiotics -   progesterone receptor modulators -   progestins -   prolactin inhibitors -   prostaglandin D2 antagonists -   protease inhibitors -   proton pump inhibitors -   psoralens -   psychotherapeutic agents -   psychotherapeutic combinations -   purine nucleosides -   pyrrolidine anticonvulsants -   quinolones -   radiocontrast agents -   radiologic adjuncts -   radiologic agents -   radiologic conjugating agents -   radiopharmaceuticals -   RANK ligand inhibitors -   recombinant human erythropoietins -   renin inhibitors -   respiratory agents -   respiratory inhalant products -   rifamycin derivatives -   salicylates -   sclerosing agents -   second generation cephalosporins -   selective estrogen receptor modulators -   selective serotonin reuptake inhibitors -   serotonin-norepinephrine reuptake inhibitors -   serotoninergic neuroenteric modulators -   sex hormone combinations -   sex hormones -   skeletal muscle relaxant combinations -   skeletal muscle relaxants -   smoking cessation agents -   somatostatin and somatostatin analogs -   spermicides -   statins -   sterile irrigating solutions -   streptomyces derivatives -   succinimide anticonvulsants -   sulfonamides -   sulfonylureas -   synthetic ovulation stimulants -   tetracyclic antidepressants -   tetracyclines -   therapeutic radiopharmaceuticals -   thiazide diuretics -   thiazolidinediones -   thioxanthenes -   third generation cephalosporins -   thrombin inhibitors -   thrombolytics -   thyroid drugs -   tocolytic agents -   topical acne agents -   topical agents -   topical anesthetics -   topical anti-infectives -   topical antibiotics -   topical antifungals -   topical antihistamines -   topical antipsoriatics -   topical antivirals -   topical astringents -   topical debriding agents -   topical depigmenting agents -   topical emollients -   topical keratolytics -   topical steroids -   topical steroids with anti-infectives -   toxoids -   triazine anticonvulsants -   tricyclic antidepressants -   trifunctional monoclonal antibodies -   tumor necrosis factor (TNF) inhibitors -   tyrosine kinase inhibitors -   ultrasound contrast media -   upper respiratory combinations -   urea anticonvulsants -   urinary anti-infectives -   urinary antispasmodics -   urinary pH modifiers -   uterotonic agents -   vaccine -   vaccine combinations -   vaginal anti-infectives -   vaginal preparations -   vasodilators -   vasopressin antagonists -   vasopressors -   VEGF/VEGFR inhibitors -   viral vaccines -   viscosupplementation agents -   vitamin and mineral combinations -   vitamins     Diagnostic Tests -   17-Hydroxyprogesterone -   ACE (Angiotensin I converting enzyme) -   Acetaminophen -   Acid phosphatase -   ACTH -   Activated clotting time -   Activated protein C resistance -   Adrenocorticotropic hormone (ACTH) -   Alanine aminotransferase (ALT) -   Albumin -   Aldolase -   Aldosterone -   Alkaline phosphatase -   Alkaline phosphatase (ALP) -   Alpha1-antitrypsin -   Alpha-fetoprotein -   Alpha-fetoprotien -   Ammonia levels -   Amylase -   ANA (antinuclear antbodies) -   ANA (antinuclear antibodies) -   Angiotensin-converting enzyme (ACE) -   Anion gap -   Anticardiolipin antibody -   Anticardiolipin antivbodies (ACA) -   Anti-centromere antibody -   Antidiuretic hormone -   Anti-DNA -   Anti-Dnase-B -   Anti-Gliadin antibody -   Anti-glomerular basement membrane antibody -   Anti-HBc (Hepatitis B core antibodies -   Anti-HBs (Hepatitis B surface antibody -   Antiphospholipid antibody -   Anti-RNA polymerase -   Anti-Smith (Sm) antibodies -   Anti-Smooth Muscle antibody -   Antistreptolysin O (ASO) -   Antithrombin III -   Anti-Xa activity -   Anti-Xa assay -   Apolipoproteins -   Arsenic -   Aspartate aminotransferase (AST) -   B12 -   Basophil -   Beta-2-Microglobulin -   Beta-hydroxybutyrate -   B-HCG -   Bilirubin -   Bilirubin, direct -   Bilirubin, indirect -   Bilirubin, total -   Bleeding time -   Blood gases (arterial) -   Blood urea nitrogen (BUN) -   BUN -   BUN (blood urea nitrogen) -   CA 125 -   CA 15-3 -   CA 19-9 -   Calcitonin -   Calcium -   Calcium (ionized) -   Carbon monoxide (CO) -   Carcinoembryonic antigen (CEA) -   CBC -   CEA -   CEA (carcinoembryonic antigen) -   Ceruloplasmin -   CH50Chloride -   Cholesterol -   Cholesterol, HDL -   Clot lysis time -   Clot retraction time -   CMP -   CO2 -   Cold agglutinins -   Complement C3 -   Copper -   Corticotrophin releasing hormone (CRH) stimulation test -   Cortisol -   Cortrosyn stimulation test -   C-peptide -   CPK (Total) -   CPK-MB -   C-reactive protein -   Creatinine -   Creatinine kinase (CK) -   Cryoglobulins -   DAT (Direct antiglobulin test) -   D-Dimer -   Dexamethasone suppression test -   DHEA-S -   Dilute Russell viper venom -   Elliptocytes -   Eosinophil -   Erythrocyte sedimentation rate (ESR) -   Estradiol -   Estriol -   Ethanol -   Ethylene glycol -   Euglobulin lysis -   Factor V Leiden -   Factor VIII inhibitor -   Factor VIII level -   Ferritin -   Fibrin split products -   Fibrinogen -   Folate -   Folate (serum -   Fractional excretion of sodium (FENA) -   FSH (follicle stimulating factor) -   FTA-ABS -   Gamma glutamyl transferase (GGT) -   Gastrin -   GGTP (Gamma glutamyl transferase) -   Glucose -   Growth hormone -   Haptoglobin -   HBeAg (Hepatitis Be antigen) -   HBs-Ag (Hepatitis B surface antigen) -   Helicobacter pylori -   Hematocrit -   Hematocrit (HCT) -   Hemoglobin -   Hemoglobin Al C -   Hemoglobin electrophoresis -   Hepatitis A antibodies -   Hepatitis C antibodies -   IAT (Indirect antiglobulin test) -   Immunofixation (IFE) -   Iron -   Lactate dehydrogenase (LDH) -   Lactic acid (lactate) -   LDH -   LH (Leutinizing hormone -   Lipase -   Lupus anticoagulant -   Lymphocyte -   Magnesium -   MCH (mean corpuscular hemoglobin -   MCHC (mean corpuscular hemoglobin concentration) -   MCV (mean corpuscular volume) -   Methylmalonate -   Monocyte -   MPV (mean platelet volume) -   Myoglobin -   Neutrophil -   Parathyroid hormone (PTH) -   Phosphorus -   Platelets (plt) -   Potassium -   Prealbumin -   Prolactin -   Prostate specific antigen (PSA) -   Protein C -   Protein S -   PSA (prostate specific antigen) -   PT (Prothrombin time) -   PTT (Partial thromboplastin time) -   RDW (red cell distribution width) -   Renin -   Rennin -   Reticulocyte count -   reticulocytes -   Rheumatoid factor (RF) -   Sed Rate -   Serum glutamic-pyruvic transaminase (SGPT -   Serum protein electrophoresis (SPEP) -   Sodium -   T3-resin uptake (T3RU) -   T4, Free -   Thrombin time -   Thyroid stimulating hormone (TSH) -   Thyroxine (T4 -   Total iron binding capacity (TIBC) -   Total protein -   Transferrin -   Transferrin saturation -   Triglyceride (TG) -   Troponin -   Uric acid -   Vitamin B12 -   White blood cells (WBC) -   Widal test

As several examples, the fluid composition 218 can be an inhalation anesthetic, a drug, or a diagnostic test material. Any of these fluid compositions 218 can be an injectable material, a volatile material capable of being inhaled, or otherwise capable of being introduced into a subject.

In the embodiment of FIG. 7 in particular, the pharmaceutical package 210 is a syringe. The syringe can comprise a syringe barrel 250 and a plunger 258. The wall 214 can define at least a portion of the syringe barrel 250. The plunger 258 can be a relatively sliding part of the syringe, with respect to the syringe barrel 250. The term “syringe,” however, is broadly defined to include cartridges, injection “pens,” and other types of barrels or reservoirs adapted to be assembled with one or more other components to provide a functional syringe. “Syringe” is also broadly defined to include related articles such as auto-injectors, which provide a mechanism for dispensing the contents.

Another aspect of the invention illustrated by FIGS. 24-26 is an article such as any of the pharmaceutical packages or other vessels 210 including a wall 214, a fluid composition 218, a barrier coating or layer 288, and a protective coating 286.

The wall 214 has an inner or interior surface 254.

The fluid composition 218 is contained in the lumen 212 and has a pH between 5 and 9.

The barrier coating or layer 288 is made at least in part of SiO_(x), wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick. The barrier coating or layer 288 of SiO_(x) has an interior surface 220 facing the lumen 212 and an outer surface 222 facing the wall inner or interior surface 254. The barrier coating or layer 288 is effective to reduce the ingress of atmospheric gas into the lumen 212, compared to an uncoated container otherwise the same as the pharmaceutical package or other vessel 210.

The protective coating 286 is made at least in part of a saccharide. The protective coating 286 has an interior surface 224 facing the lumen 212 and an outer surface 226 facing the interior surface 254 of the barrier coating or layer 288. Other specific examples of precursors within this broad definition are provided elsewhere in this specification.

The rate of erosion, dissolution, or leaching (different names for related concepts) of the protective coating 286, if directly contacted by the fluid composition 218, is less than the rate of erosion of the barrier coating or layer 288, if directly contacted by the fluid composition 218.

The protective coating 286 is effective to isolate the fluid composition 218 from the barrier coating or layer 288, at least for sufficient time to allow the barrier coating to act as a barrier during the shelf life of the pharmaceutical package or other vessel 210.

Still another aspect of the invention, again illustrated by FIGS. 7 to 9, is a pharmaceutical package or other vessel 210 including a thermoplastic wall 214 having an inner or interior surface 220 enclosing a lumen 212. A fluid composition 218 contained in the lumen 212 has a pH greater than 5.

A barrier coating or layer 286 of SiO_(x), in which x is between 1.5 and 2.9, is applied by plasma enhanced chemical vapor deposition (PECVD) directly or indirectly to the thermoplastic wall 214 so that in the filled pharmaceutical package or other vessel 210 the barrier coating or layer 286 is located between the inner or interior surface 220 of the thermoplastic wall 214 and the fluid composition 218. The barrier coating or layer 286 of SiO_(x) is supported by the thermoplastic wall 214. The barrier coating or layer 286 has the characteristic of being subject to being measurably diminished in barrier improvement factor in less than six months as a result of attack by the fluid composition 218. The barrier coating or layer 286 as described elsewhere in this specification, or in U.S. Pat. No. 7,985,188, can be used in any embodiment.

The barrier improvement factor (BIF) of the barrier layer can be determined by providing two groups of identical containers, adding a barrier layer to one group of containers, testing a barrier property (such as the rate of outgassing in micrograms per minute or another suitable measure) on containers having a barrier, doing the same test on containers lacking a barrier, and taking a ratio of the properties of the materials with versus without a barrier. For example, if the rate of outgassing through the barrier is one-third the rate of outgassing without a barrier, the barrier has a BIF of 3.

A protective coating 286 of a saccharide is applied by directly or indirectly to the barrier coating or layer 288 so it is located between the barrier coating or layer 288 and the fluid composition 218 in the finished article. The protective coating 286 is supported by the thermoplastic wall 214. The protective coating 286 is effective to keep the barrier coating or layer 288 at least substantially undissolved as a result of attack by the fluid composition 218 for a period of at least six months.

Any embodiment of FIGS. 24-26 can further optionally include a lubricity layer 287. The lubricity layer 287 can be applied between the protective coating and the lumen. Lubricity layers 287 as described in U.S. Pat. No. 7,985,188 can be used in any embodiment.

Any embodiment of FIGS. 24-26 can further optionally include a further coating applied adjacent to the inner surface of the protective coating, the further coating having an outer surface facing the interior surface of the thermoplastic wall and an inner surface facing the lumen.

Optionally, any embodiment of FIGS. 24-26 can further include a fluid composition 218 in contact with the protective coating

The protective and lubricity layers 286 and 287 of any embodiment of FIGS. 24-26 can be either separate layers with a sharp transition or a single, graduated layer that transitions between the protective coating 286 and the lubricity layer 287, without a sharp interface between them.

Optionally, in any embodiment of FIGS. 24-26 the silicon dissolution rate by a 50 mM potassium phosphate buffer diluted in water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. % polysorbate-80 surfactant, (measured in the absence of the medicament, to avoid changing the dissolution reagent), at 40° C., is less than 170 ppb/day. (Polysorbate-80 is a common ingredient of pharmaceutical preparations, available for example as Tween®-80 from Uniqema Americas LLC, Wilmington, Del.) As will be seen from the working examples, the silicon dissolution rate is measured by determining the total silicon leached from the vessel into its contents, and does not distinguish between the silicon derived from the protective coating 286, the lubricity layer 287, the barrier coating or layer 288, or other materials present.

Optionally, in any embodiment of FIGS. 24-26 the silicon dissolution rate is less than 160 ppb/day, or less than 140 ppb/day, or less than 120 ppb/day, or less than 100 ppb/day, or less than 90 ppb/day, or less than 80 ppb/day. Optionally, in any embodiment of FIGS. 24-26 the silicon dissolution rate is more than 10 ppb/day, or more than 20 ppb/day, or more than 30 ppb/day, or more than 40 ppb/day, or more than 50 ppb/day, or more than 60 ppb/day. Any minimum rate stated here can be combined with any maximum rate stated here, as an alternative embodiment of the invention of FIGS. 7 TO 9.

Optionally, in any embodiment of FIGS. 24-26 the total silicon content of the protective coating and barrier coating, upon dissolution into a test composition with a pH of 8 from the vessel, is less than 66 ppm, or less than 60 ppm, or less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.

Optionally, in any embodiment of FIGS. 24-26 the calculated shelf life of the package (total Si/Si dissolution rate) is more than six months, or more than 1 year, or more than 18 months, or more than 2 years, or more than 2½ years, or more than 3 years, or more than 4 years, or more than 5 years, or more than 10 years, or more than 20 years. Optionally, in any embodiment of FIGS. 24-26 the calculated shelf life of the package (total Si/Si dissolution rate) is less than 60 years.

Any minimum time stated here can be combined with any maximum time stated here, as an alternative embodiment of the invention of FIGS. 7 TO 9.

Optionally, in any embodiment of FIGS. 24-26, the thermoplastic wall is a syringe barrel. A plunger is positioned for sliding in the barrel and a lubricity coating or layer is present on at least a portion of the plunger.

Optionally, in any embodiment of FIGS. 24-26, the lubricity coating or layer is configured to provide a lower piston sliding force or breakout force than the uncoated substrate.

Optionally, in any embodiment of FIGS. 24-26, the lubricity layer has one of the atomic ratios previously defined for the lubricity and/or protective coating, measured by X-ray photoelectron spectroscopy (XPS). The lubricity layer has a thickness by transmission electron microscopy (TEM) between 10 and 500 nm; the lubricity layer deposited by plasma enhanced chemical vapor deposition (PECVD) under conditions effective to form a coating from a precursor selected from a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.

Even another aspect of the invention, exemplified in FIGS. 7 TO 9, is a composite material including a substrate such as a wall 214, a barrier coating or layer 288 disposed on the substrate or wall 214, and a passivation layer or protective coating 286 on the barrier layer or coating 288. Several examples of articles made from such a composite material are a syringe barrel, a vial, and a medical device of any kind. The saccharide passivation layer or protective coating 286 is deposited as explained below.

PECVD Apparatus and Methods for Protective Coating

Suitable methods and apparatus for applying a barrier or lubricity coating or layer such as 90 to a substrate such as the vessel 80 (FIG. 1) or a vial are described, for example, in U.S. Pat. No. 7,985,188 or the EP applications cited in paragraph [002], under conditions effective to form a coating or layer.

Another embodiment is a vessel such as the vessel 80 (FIG. 1) including a lumen defined by a surface defining a substrate. A protective coating or layer is present on at least a portion of the substrate, typically deposited over an SiO_(x) barrier layer to protect the barrier layer from dissolution. The protective coating or layer is made by the previously defined process.

Still another embodiment is a chemical vapor deposition apparatus such as the apparatus 28 illustrated in FIG. 5 (or any other illustrated coating apparatus, such as the apparatus illustrated in FIGS. 1-4).

Referring now to FIG. 5, suitable chemical vapor deposition apparatus is shown.

Referring to FIG. 7, yet another embodiment is a syringe such as 252 comprising a plunger 258, a barrel 250, and a protective coating or layer on the inner or interior surface 264. The barrel 250 is a vessel and has an inner or interior surface 264 defining the vessel lumen 274 and receiving the plunger 258 for sliding. The vessel inner or interior surface 264 is a substrate. A protective coating or layer can be applied on the substrate 264, the plunger 258, or both, by chemical vapor deposition. In addition to this protective coating or layer, the syringe may contain one or more other coatings or layers, for example an SiO_(x) barrier coating or layer. Said additional coating(s) or layer(s) may be located under the lubricity and/or barrier coating or layer, i.e. nearer to the barrel of the syringe.

For any embodiment of a syringe such as 252, in particular a syringe that is stored or intended to be stored for an extended time while prefilled, the plunger 258 optionally is provided with a lubricity layer, at least on its surface in contact with the barrel interior surface 264, and the barrel interior surface 264 is provided with an SiO_(x) barrier layer protected by a protective coating or layer wherever it is in contact or likely to be in contact with a fluid pharmaceutical composition contained in the syringe. An advantage of this construction is that the protective coating or layer, which is in contact with the fluid pharmaceutical composition when the syringe is stored prefilled, can be optimized for protection of the SiO_(x) barrier layer, while the lubricity layer, which is located where the plunger typically contacts the inner surface 264 at a fixed location during storage, can be optimized for lubricity. The lubricity coating or layer on the plunger is in the right position to prevent “sticktion” during storage and to continue to lower the friction between the plunger and barrel when the plunger is advanced, and if applied by CVD is contemplated to be less subject to displacement by the force exerted by the plunger on the barrel than traditional silicon oil coatings or layers and more uniformly applied as a uniform coating rather than as isolated droplets of liquid. As a further option, an adhesion layer or coating of SiO_(x)C_(y) can be applied to the substrate and the barrier layer can be applied to the adhesion layer to improve adhesion of the SiO_(x) barrier layer or coating to the substrate.

A concern of converting from glass to plastic syringes centers around the potential for leachable materials from plastics. With plasma coating technology, the coatings or layers derived from non-metal gaseous precursors, for example HMDSO or OMCTS or other organosilicon compounds, will itself contain no trace metals and function as a barrier to inorganic, metals and organic solutes, preventing leaching of these species from the coated substrate into syringe fluids. In addition to leaching control of plastic syringes, the same plasma protective coating or layer technology offers potential to provide a solute barrier to the plunger tip, typically made of elastomeric plastic compositions containing even higher levels of leachable organic oligomers and catalysts.

Moreover, certain syringes prefilled with synthetic and biological pharmaceutical formulations are very oxygen and moisture sensitive. A critical factor in the conversion from glass to plastic syringe barrels will be the improvement of plastic oxygen and moisture barrier performance. The plasma protective coating or layer technology is suitable to maintain the SiO_(x) barrier coating or layer for protection against oxygen and moisture over an extended shelf life.

Even another embodiment is a plunger 258 for a syringe 252, comprising a piston or tip, a protective coating or layer, and a push rod. The piston or tip has a front face, a generally cylindrical side face that slides within the barrel 250, comprising a substrate, and a back portion. The side face is configured to movably seat within a syringe barrel. The protective coating or layer is on the substrate and is a lubricity and/or protective coating interfacing with the side face. The lubricity and/or protective coating is produced from a chemical vapor deposition (CVD) process employing the previously defined precursor feed or process gas. The push rod engages the back portion of the piston and is configured for advancing the piston in a syringe barrel.

Even another embodiment is a medical or diagnostic kit including a vessel having a coating or layer as defined in any embodiment herein on a substrate as defined in any embodiment above. Optionally, the kit additionally includes a medicament or diagnostic agent which is contained in the vessel with a protective coating in contact with the coating or layer; and/or a hypodermic needle, double-ended needle, or other delivery conduit; and/or an instruction sheet.

Other aspects of the invention include any one or more of the following:

Use of the protective coating or layer according to any embodiment described above for treating a surface and thereby preventing or reducing mechanical and/or chemical effects of the surface on a compound or composition in contact with the protective coating or layer;

Use of the coating or layer according to any described embodiment as a lubricity and/or protective coating;

Use of the coating or layer according to any described embodiment for protecting a compound or composition contacting the protective coating or layer against mechanical and/or chemical effects of the surface of the vessel material without a protective coating;

Use of the coating or layer according to any described embodiment for preventing or reducing precipitation and/or clotting or platelet activation of a compound or a component of the composition in contact with the coating or layer.

As one option, the compound or a component of the composition is insulin, and precipitation of the insulin is prevented or reduced. As another option, the compound or a component of the composition is blood or a blood fraction, and blood clotting or platelet activation is prevented or reduced. As still another option, the vessel with a protective coating is a blood collection tube. Optionally, the blood collection tube can contain an agent for preventing blood clotting or platelet activation, for example ethylenediamineteetraacetic acid (EDTA), a sodium salt thereof, or heparin.

Additional options for use of the invention include any one or more of the following:

Use of a coated substrate according to any described embodiment, for example a vessel such as a sample collection tube, for example a blood collection tube and/or a closed-ended sample collection tube; a vial; a conduit; a cuvette; or a vessel part, for example a stopper; or a syringe, or a syringe part, for example a barrel or piston for reception and/or storage and/or delivery of a compound or composition.

The use of a coated substrate according to any described embodiment is contemplated for storing insulin.

The use of a coated substrate according to any described embodiment is contemplated for storing blood. Optionally, the stored blood is viable for return to the vascular system of a patient.

Use of a coating or layer according to any described embodiment is contemplated as (i) a lubricity coating having a lower frictional resistance than the uncoated surface; and/or (ii) a protective coating preventing dissolution of the barrier coating in contact with a fluid, and/or (iii) a hydrophobic layer that is more hydrophobic than the uncoated surface.

Other aspects of the invention include any of the uses defined above in the summary section.

DETAILED DESCRIPTION

The following is a more detailed description of the invention. It starts with a general description of the present invention, then describes the equipment suitable to prepare the protective coating or layer of the present invention and subsequently describes the protective coating or layer embodiments, the coated pharmaceutical packages or other vessels, and the methods for their production.

Substrate

The substrate of the protective coating or layer in any embodiment is typically a vessel having a surface made of plastic (for example the inner or interior surface of a plastic syringe or vial). Typical plastic substrates are listed elsewhere in the present description and in referenced patents. Particularly suitable substrates in the context of the present invention are COC (cyclic olefin copolymer), COP (cyclic olefin polymer), PET (polyethylene terephthalate), and polypropylene, with COC being specifically suitable.

Barrier Layer

The barrier coating or layer for any embodiment defined in this specification (unless otherwise specified in a particular instance) is a coating or layer, optionally applied by PECVD as indicated in U.S. Pat. No. 7,985,188. The barrier layer optionally is characterized as an “SiO_(x)” coating, and contains silicon, oxygen, and optionally other elements, in which x, the ratio of oxygen to silicon atoms, is from about 1.5 to about 2.9, or 1.5 to about 2.6, or about 2. These alternative definitions of x apply to any use of the term SiO_(x) in this specification. The barrier coating or layer is applied, for example to the interior of a pharmaceutical package or other vessel, for example a sample collection tube, a syringe barrel, a vial, or another type of vessel.

Protective Layer

The protective layer is applied over at least a portion of the SiO_(x) layer to protect the SiO_(x) layer from contents stored in a vessel, where the contents otherwise would be in contact with the SiO_(x) layer.

Precursors for Protective Coating or Layer

The present lubricating or protective coating or layer is a saccharide coupled to the SiO_(x) barrier layer by a substituted silane coupling agent.

The silane coupling agent can be, for example, trimethoxysilylpropyl isocyanate. The silane functional group interacts with an SiO_(x) barrier layer. The isocyanate functional group reacts with a hydroxyl group of the saccharide to provide a urethane linkage. The coupling agent thus functions to anchor the saccharide, which provides a lubricated surface in an aqueous environment, in this case the contents of the container, to the barrier layer to prevent the saccharide from dispersing in the aqueous environment.

The silane coupling agent can instead be, for example, 3-Aminopropyltriethoxysilane (APTES). The silane functional group interacts with an SiO_(x) barrier layer. The amino functional group reacts with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (NHS) in the presence of haluronic acid (HA). EDC/NHS can chemically graft HA onto APTES.

The coupling agent thus functions to anchor the saccharide, which provides a lubricated surface in an aqueous environment, in this case the contents of the container, to the barrier layer to prevent the saccharide from dispersing in the aqueous environment.

The saccharide precursor for use to provide a protective coating or layer is contemplated to be a water soluble or dispersible saccharide, dispersed or dissolved in water. The precursor may be present as from about 0.05% to about 15% by weight, or from about 0.2 to about 10% by weight, or from about 0.5% to about 6% by weight, or from about 1.5% to about 3% by weight, of the composition.

The saccharide can be selected from the group consisting of mono- and polysaccharides (or, more broadly, carbohydrates) and their derivatives. Saccharide (which for the present purpose includes disaccharide and higher saccharide) materials contemplated for use herein include any sugar, for example sorbitan, corn starch, other starches, and saccharide gums. Saccharide gums contemplated for use herein include agar, Arabic, xanthan (for example, KELZAN industrial grade xanthan gum, available from the Kelco Div. of Merck & Co, Inc. of Rahway, N.J.), pectin, alginate, tragacanath, dextran, and other gums. Derivative saccharides contemplated for use herein include cellulose acetates, cellulose nitrates, methylcellulose, and carboxymethylcellulose. Hemi-cellulose saccharides contemplated for use herein include d-gluco-d-mannans, d-galacto-d-gluco-d-mannans, and others. Haluronic acid is also specifically contemplated, as is sorbitan.

Also contemplated herein as saccharides are alkylcelluloses or carboxyalkylcelluloses, their low- and medium-viscosity alkali metal salts (e.g. sodium carboxymethylcellulose, or “CMC”), cellulose ethers, and nitrocellulose. Examples of such saccharides include KLUCEL hydroxypropylcellulose; AQUALON CMC 7L sodium carboxymethylcellulose, and NATROSOL hydroxyethylcellulose. These are all commercially available from Aqualon Company of Hopewell, Va. Saccharides contemplated herein further include ethylcellulose, available from Hercules of Wilmington, Del.; METHOCEL cellulose ethers, available from Dow Chemical Co., Midland, Mich.; and nitrocellulose, which is also available from Hercules.

Method of Applying a Lubricity Coating or Layer

A method of applying a lubricity coating or layer derived from an organosilicon precursor, and the resulting protective coating or layer and coated item are described for example in U.S. Pat. No. 7,985,188. A “lubricity coating” or any similar term is generally defined as a coating or layer that reduces the frictional resistance of the coated surface, relative to the uncoated surface, which can include a coating which is a saccharide or a coating as described in U.S. Pat. No. 7,985,188. If the coated object is a syringe (or syringe part, for example syringe barrel) or any other item generally containing a plunger or movable part in sliding contact with the coated surface, the frictional resistance has two main aspects—breakout force and plunger sliding force.

It should be understood that a coating optionally can be both a lubricity coating or layer and a protective coating or layer, respectively as explained in this description.

Barrier Coating or Layer

Any barrier coating or layer described in U.S. Patent No. 7,985,188 is contemplated for use in any embodiment of the present invention.

Measurement of Coating Thickness

The thickness of a coating or layer such as the protective coating or layer, the barrier coating or layer, the lubricity coating or layer, and/or a composite of any two or more of these layers can be measured, for example, by transmission electron microscopy (TEM). An exemplary TEM image for an SiO₂ barrier coating or layer is shown in FIG. 6.

The TEM can be carried out, for example, as follows. Samples can be prepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Either the samples can be first coated with a thin layer of carbon (50-100 nm thick) and then coated with a sputtered coating or layer of platinum (50-100 nm thick) using a K575X Emitech protective coating or layer system, or the samples can be coated directly with the protective sputtered Pt layer. The coated samples can be placed in an FEI FIB200 FIB system. An additional coating or layer of platinum can be FIB-deposited by injection of an organometallic gas while rastering the 30 kV gallium ion beam over the area of interest. The area of interest for each sample can be chosen to be a location half way down the length of the syringe barrel. Thin cross sections measuring approximately 15 μm (“micrometers”) long, 2 μm wide and 15 μm deep can be extracted from the die surface using an in-situ FIB lift-out technique. The cross sections can be attached to a 200 mesh copper TEM grid using FIB-deposited platinum. One or two windows in each section, measuring about 8 μm wide, can be thinned to electron transparency using the gallium ion beam of the FEI FIB.

Cross-sectional image analysis of the prepared samples can be performed utilizing either a Transmission Electron Microscope (TEM), or a Scanning Transmission Electron Microscope (STEM), or both. All imaging data can be recorded digitally. For STEM imaging, the grid with the thinned foils can be transferred to a Hitachi HD2300 dedicated STEM. Scanning transmitted electron images can be acquired at appropriate magnifications in atomic number contrast mode (ZC) and transmitted electron mode (TE). The following instrument settings can be used.

Scanning Transmission Electron Microscope Instrument Manufacturer/Model Hitachi HD2300 Accelerating Voltage 200 kV Objective Aperture #2 Condenser Lens 1 Setting 1.672 Condenser Lens 2 Setting 1.747 Approximate Objective 5.86 Lens Setting ZC Mode Projector Lens 1.149 TE Mode Projector Lens 0.7 Image Acquisition Pixel Resolution 1280 × 960 Acquisition Time 20 sec.(×4

For TEM analysis the sample grids can be transferred to a Hitachi HF2000 transmission electron microscope. Transmitted electron images can be acquired at appropriate magnifications. The relevant instrument settings used during image acquisition can be those given below.

Instrument Transmission Electron Microscope Manufacturer/Model Hitachi HF2000 Accelerating Voltage 200 kV Condenser Lens 1 0.78 Condenser Lens 2 0 Objective Lens 6.34 Condenser Lens Aperture #1 Objective Lens Aperture #3 for imaging Selective Area Aperture N/A for SAD Liquid-applied Protective Coating or Layer

Another example of a suitable barrier or other type of protective coating or layer, usable in conjunction with the PECVD-applied protective coating or layer or other PECVD treatment as disclosed here, can be a liquid barrier, lubricant, surface energy tailoring, or protective coating or layer 90 applied to the inner or interior surface of a pharmaceutical package or other vessel, either directly or with one or more intervening PECVD-applied coatings or layers described in this specification, for example SiO_(x), a lubricity coating or layer and/or a protective coating or layer, or both.

A suitable liquid barrier, lubricity, or protective coating or layer 90 also optionally can be applied, for example, by applying a liquid monomer or other polymerizable or curable material to the inner or interior surface of the vessel 80 and curing, polymerizing, or crosslinking the liquid monomer to form a solid polymer, or by applying a solvent-dispersed polymer to the surface 88 and removing the solvent.

Any of the above methods can include as a step forming a protective coating or layer 90 on the interior 88 of a vessel 80 via the vessel port 92 at a processing station or device 28. One example is applying a liquid protective coating or layer, for example of a curable monomer, prepolymer, or polymer dispersion, to the inner or interior surface 88 of a vessel 80 and curing it to form a film that physically isolates the contents of the vessel 80 from its inner or interior surface 88. The prior art describes polymer protective coating or layer technology as suitable for treating plastic blood collection tubes. For example, the acrylic and polyvinylidene chloride (PVdC) protective coating materials and methods described in U.S. Pat. No. 6,165,566, which is hereby incorporated by reference, optionally can be used.

Any of the above methods can also include as a step forming a coating or layer on the exterior outer wall of a vessel 80. The exterior coating or layer optionally can be a barrier coating or layer, optionally an oxygen barrier coating or layer, or optionally a water barrier coating or layer. The exterior coating or layer can also be an armor layer that protects the outer wall of a vessel 80. One example of a suitable exterior coating or layer is polyvinylidene chloride, which functions both as a water barrier and an oxygen barrier. Optionally, the exterior coating or layer can be applied as a water-based coating or layer. The exterior coating or layer optionally can be applied by dipping the vessel in it, spraying it on the pharmaceutical package or other vessel, or other expedients.

PECVD Treated Pharmaceutical Packages or Other Vessels

Coated Pharmaceutical Packages or Other Vessels

Pharmaceutical packages or other vessels, such as a prefilled syringe (schematically shown in FIG. 7) or a vial (schematically shown in FIGS. 8 and 9) are contemplated having a barrier coating or layer such as 288 at least partially covered by a protective coating or layer such as 286.

The pharmaceutical package 210 as shown in any embodiment, for example FIGS. 7 TO 9, comprises a vessel or vessel part such as 250; optionally a barrier coating or layer such as 288 on the vessel or vessel part; a protective coating or layer such as 286 on the vessel, vessel part, or barrier coating or layer; and a pharmaceutical composition or preparation such as 218 contained within the vessel.

The barrier coating or layer such as 288 can be an SiO_(x) barrier coating or layer applied as described in any embodiment of this specification or in U.S. Pat. No. 7,985,188. For example, the barrier coating or layer such as 288 of any embodiment can be applied at a thickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150 nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm, or at least 800 nm, or at least 900 nm. The barrier coating or layer can be up to 1000 nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick. Specific thickness ranges composed of any one of the minimum thicknesses expressed above, plus any equal or greater one of the maximum thicknesses expressed above, are expressly contemplated. The thickness of the SiO_(x) or other barrier coating or layer can be measured, for example, by transmission electron microscopy (TEM), and its composition can be measured by X-ray photoelectron spectroscopy (XPS). The protective coating or layer described herein can be applied to a variety of pharmaceutical packages or other vessels made from plastic or glass, for example to plastic tubes, vials, and syringes.

The protective coating or layer such as 286 can be a saccharide protective coating or layer applied as described in any embodiment of this specification.

Vessel Made of Glass

Another embodiment is a pharmaceutical package 210 as shown in any embodiment, for example FIGS. 7 TO 9, comprising a vessel or vessel part such as 214 or 250 made of glass; optionally a barrier coating or layer such as 288 on the vessel or vessel part; a protective coating or layer such as 286 on the vessel, vessel part, or barrier coating or layer; and a pharmaceutical composition or preparation such as 218 contained within the vessel. In this embodiment the barrier coating or layer is optional because a glass vessel wall in itself is an extremely good barrier layer. It is contemplated to optionally provide a barrier layer primarily to provide isolation: in other words, to prevent contact and interchange of material of any kind, such as ions of the glass or constituents of the pharmaceutical composition or preparation between the vessel wall and the contents of the vessel. The protective layer as defined in this specification is contemplated to perform the isolation function independently, at least to a degree. This protection layer is contemplated to provide a useful function on glass in contact with the pharmaceutical composition or preparation, as the present working examples show that borosilicate glass, commonly used today for pharmaceutical packaging, is dissolved by a fluid composition having a pH exceeding 5. Particularly in applications where such dissolution is disadvantageous or perceived to be disadvantageous, the present protective coatings or layers will find utility.

The vessel can be made, for example of glass of any type used in medical or laboratory applications, such as soda-lime glass, borosilicate glass, or other glass formulations. One function of a protective coating or layer on a glass vessel can be to reduce the ingress of ions in the glass, either intentionally or as impurities, for example sodium, calcium, or others, from the glass to the contents of the pharmaceutical package or other vessel, such as a reagent or blood in an evacuated blood collection tube. Alternatively, a dual functional protective/lubricity coating or layer can be used on a glass vessel in whole or in part, such as selectively at surfaces contacted in sliding relation to other parts, to provide lubricity, for example to ease the insertion or removal of a stopper or passage of a sliding element such as a piston in a syringe, as well as to provide the isolation of a protective coating or layer. Still another reason to coat a glass vessel, for example with a dual functional hydrophobic and protective coating or layer, is to prevent a reagent or intended sample for the pharmaceutical package or other vessel, such as blood, from sticking to the wall of the vessel or an increase in the rate of coagulation of the blood in contact with the wall of the vessel, as well as to provide the isolation of a protective coating or layer.

A related embodiment is a vessel as described in the previous paragraphs, in which the barrier coating or layer is made of soda lime glass, borosilicate glass, or another type of glass coating or layer on a substrate.

Vessels Generally

A vessel with a protective coating as described herein and/or prepared according to a method described herein can be used for reception and/or storage and/or delivery of a compound or composition. The compound or composition can be sensitive, for example air-sensitive, oxygen-sensitive, sensitive to humidity and/or sensitive to mechanical influences. It can be a biologically active compound or composition, for example a pharmaceutical preparation or medicament like insulin or a composition comprising insulin. In another aspect, it can be a biological fluid, optionally a bodily fluid, for example blood or a blood fraction. In certain aspects of the present invention, the compound or composition can be a product to be administrated to a subject in need thereof, for example a product to be injected, like blood (as in transfusion of blood from a donor to a recipient or reintroduction of blood from a patient back to the patient) or insulin.

A vessel with a protective coating as described herein and/or prepared according to a method described herein can further be used for protecting a compound or composition contained in its interior space against mechanical and/or chemical effects of the surface of the vessel material. For example, it can be used for preventing or reducing precipitation and/or clotting or platelet activation of the compound or a component of the composition, for example insulin precipitation or blood clotting or platelet activation.

It can further be used for protecting a compound or composition contained in its interior against the environment outside of the pharmaceutical package or other vessel, for example by preventing or reducing the entry of one or more compounds from the environment surrounding the vessel into the interior space of the vessel. Such environmental compound can be a gas or liquid, for example an atmospheric gas or liquid containing oxygen, air, and/or water vapor.

A vessel with a protective coating as described herein can also be evacuated and stored in an evacuated state. For example, the protective coating or layer allows better maintenance of the vacuum in comparison to a corresponding vessel without a protective coating. In one aspect of this embodiment, the vessel with a protective coating is a blood collection tube. The tube can also contain an agent for preventing blood clotting or platelet activation, for example EDTA or heparin.

Any of the above-described embodiments can be made, for example, by providing as the vessel a length of tubing from about 1 cm to about 200 cm, optionally from about 1 cm to about 150 cm, optionally from about 1 cm to about 120 cm, optionally from about 1 cm to about 100 cm, optionally from about 1 cm to about 80 cm, optionally from about 1 cm to about 60 cm, optionally from about 1 cm to about 40 cm, optionally from about 1 cm to about 30 cm long, and processing it with a probe electrode as described below. Particularly for the longer lengths in the above ranges, it is contemplated that relative motion between the probe and the vessel can be useful during protective coating or layer formation. This can be done, for example, by moving the vessel with respect to the probe or moving the probe with respect to the vessel.

In these embodiments, it is contemplated that the barrier coating or layer can be thinner or less complete than would be preferred to provide the high gas barrier integrity needed in an evacuated blood collection tube. In these embodiments, it is contemplated that the protective coating or layer can be thinner or less complete than would be preferred to provide the long shelf life needed to store a liquid material in contact with the barrier layer for an extended period.

As an optional feature of any of the foregoing embodiments the vessel has a central axis.

As an optional feature of any of the foregoing embodiments the vessel wall is sufficiently flexible to be flexed at least once at 20° C., without breaking the wall, over a range from at least substantially straight to a bending radius at the central axis of not more than 100 times as great as the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the bending radius at the central axis is not more than 90 times as great as, or not more than 80 times as great as, or not more than 70 times as great as, or not more than 60 times as great as, or not more than 50 times as great as, or not more than 40 times as great as, or not more than 30 times as great as, or not more than 20 times as great as, or not more than 10 times as great as, or not more than 9 times as great as, or not more than 8 times as great as, or not more than 7 times as great as, or not more than 6 times as great as, or not more than 5 times as great as, or not more than 4 times as great as, or not more than 3 times as great as, or not more than 2 times as great as, or not more than, the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the vessel wall can be a fluid-contacting surface made of flexible material.

As an optional feature of any of the foregoing embodiments the vessel lumen can be the fluid flow passage of a pump.

As an optional feature of any of the foregoing embodiments the vessel can be a blood bag adapted to maintain blood in good condition for medical use.

As an optional feature of any of the foregoing embodiments the polymeric material can be a silicone elastomer or a thermoplastic polyurethane, as two examples, or any material suitable for contact with blood, or with insulin.

In an optional embodiment, the vessel has an inner diameter of at least 2 mm, or at least 4 mm.

As an optional feature of any of the foregoing embodiments the vessel is a tube.

As an optional feature of any of the foregoing embodiments the lumen has at least two open ends.

Vessel Containing Viable Blood, Having a Protective Coating or Layer Deposited from an Organosilicon Precursor

Even another embodiment is a blood containing vessel. Several non-limiting examples of such a vessel are a blood transfusion bag, a blood sample collection vessel in which a sample has been collected, the tubing of a heart-lung machine, a flexible-walled blood collection bag, or tubing used to collect a patient's blood during surgery and reintroduce the blood into the patient's vasculature. If the vessel includes a pump for pumping blood, a particularly suitable pump is a centrifugal pump or a peristaltic pump. The vessel has a wall; the wall has an inner or interior surface defining a lumen. The inner or interior surface of the wall has an at least partial protective coating or layer of a protective layer, which optionally also presents a hydrophobic surface. The protective coating or layer can be as thin as monomolecular thickness or as thick as about 1000 nm. The vessel contains blood viable for return to the vascular system of a patient disposed within the lumen in contact with the hydrophobic layer.

An embodiment is a blood containing vessel including a wall and having an inner or interior surface defining a lumen. The inner or interior surface has an at least partial protective coating or layer that optionally also presents a hydrophobic surface. The protective coating or layer can also comprise or consist essentially of SiO_(x)C_(y) where x and y are as defined in this specification. The thickness of the hydrophobic coating or layer is within the range from monomolecular thickness to about 1000 nm thick on the inner or interior surface. The vessel contains blood viable for return to the vascular system of a patient disposed within the lumen in contact with the hydrophobic coating or layer.

Common Conditions for All Embodiments

In any embodiment contemplated here, many common conditions can be used, for example any of the following, in any combination. Alternatively, any different conditions described elsewhere in this specification or claims can be employed.

I. Coating Receiver of any Embodiment

Vessel of Any Embodiment

The vessel can be a sample collection tube, for example a blood collection tube, or a syringe, or a syringe part, for example a barrel or piston or plunger; a vial; a conduit; or a cuvette. The substrate can be a closed-ended tube, for example a medical sample collection tube. The substrate can be the inside wall of a vessel having a lumen, the lumen having a void volume of from 0.5 to 50 mL, optionally from 1 to 10 mL, optionally from 0.5 to 5 mL, optionally from 1 to 3 mL. The substrate surface can be part or all of the inner or interior surface of a vessel having at least one opening and an inner or interior surface, and wherein the gaseous reactant, also known in any embodiment as a precursor feed, fills the interior lumen of the vessel and the plasma can be generated in part or all of the interior lumen of the vessel.

Syringe and Parts

The substrate can be a syringe barrel. The syringe barrel can have a plunger sliding surface and the protective coating or layer can be disposed on at least a portion of the plunger sliding surface. The protective coating or layer can be a lubricity and/or protective coating. The lubricity and/or protective coating or layer can be on the barrel inner or interior surface. The lubricity and/or protective coating or layer can be on the plunger. In a particular aspect, the substrate is a staked needle syringe or part of a staked needle syringe.

Vessel to Receive Stopper

The substrate can be a stopper receiving surface in the mouth of a vessel. The substrate can be a generally conical or cylindrical inner or interior surface of an opening of a vessel adapted to receive a stopper.

Stopper

The substrate can be a sliding surface of a stopper. The substrates can be coated by providing a multiplicity of the stoppers located in a single substantially evacuated vessel. The chemical vapor deposition can be plasma-enhanced chemical vapor deposition and the stopper can be contacted with the plasma. The chemical vapor deposition can be plasma-enhanced chemical vapor deposition. The plasma can be formed upstream of the stopper, producing plasma product, and the plasma product can be contacted with the stopper.

A closure can define a substrate coated with a protective coating or layer, optionally a stopper coated with a lubricity and/or protective coating. The substrate can be a closure seated in a vessel defining a lumen and a surface of the closure facing the lumen can be coated with the protective coating or layer.

The protective coating or layer can be effective to reduce the transmission of a metal ion constituent of the stopper into the lumen of the vessel.

Substrate of Any Embodiment

The substrate can be a vessel wall. A portion of the vessel wall in contact with a wall-contacting surface of a closure can be coated with the protective coating or layer. The protective coating or layer can be a composite of material having first and second layers. The first coating or layer can interface with the elastomeric stopper. The first layer of the protective coating or layer can be effective to reduce the transmission of one or more constituents of the stopper into the vessel lumen. The second protective coating or layer can interface with the inner wall of the vessel. The second layer can be effective to reduce friction between the stopper and the inner wall of the vessel when the stopper is seated on the vessel.

Alternatively, the first and second layers of any embodiment can be defined by a protective coating or layer of graduated properties containing carbon and hydrogen, in which the proportions of carbon and hydrogen are less in the first coating or layer (applied to the substrate) than in the second coating or layer (exposed to the contents of the vessel).

The protective coating or layer of any embodiment can be applied by plasma enhanced chemical vapor deposition.

The substrate of any embodiment can comprise glass, alternatively a polymer, alternatively a polycarbonate polymer, alternatively an olefin polymer, alternatively a cyclic olefin copolymer, alternatively a polypropylene polymer, alternatively a polyester polymer, alternatively a polyethylene terephthalate polymer, alternatively a polyethylene naphthalate polymer, alternatively a combination, composite or blend of any two or more of the above materials.

EXAMPLE Polysaccharide-Grafted SiO_(x)-Coated Plastic Syringe Barrel

3-Aminopropyltriethoxysilane (APTES) grafting. (Method 1-Step 1)

To a freshly SiO_(x)-plasma coated COP syringe 1 mL staked needle syringe barrel, under vacuum, APTES (Sigma-Aldrich) vapor is pumped through the syringe barrel and allowed to react with and be deposited on the SiO_(x) surface for 2 h, ideally resulting in a monolayer. During the reaction, a low pressure is maintained to minimize the condensation of microscopic droplets of APTES on the surfaces. Following the deposition, covalent APTES grafting was done by annealing the surface in a vacuum oven for 30 min at 80° C.

Haluronic Acid (HA) Grafting (Method 1-Step 2)

A 3 mg/mL HA (average MW=1.6 MDa, Sigma-Aldrich) solution is put into the APTES-grafted SiO_(x) surface barrel interior for 3 h. The right amounts of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (NHS) (Sigma-Aldrich) were added into the HA solution to bring the EDC and NHS concentrations to 1 M for each component (50/50 EDC/NHS mixture). EDC/NHS can chemically graft HA onto APTES as well as cross-link the grafted HA layer, forming a gel-like HA layer. The interior syringe barrel surface is then rinsed thoroughly using phosphate buffered saline (PBS) buffer and capped to prevent dessication of bound water to the grafted polysaccharide.

Adapted from Jing Yu, Xavier Banquy, George W. Greene, Daniel D. Lowrey, and Jacob N. lsraelachvili, The Boundary Lubrication of Chemically Grafted and Cross-Linked Hyaluronic Acid in Phosphate Buffered Saline and Lipid Solutions Measured by the Surface Forces Apparatus, Langmuir 2012, 28, 2244-2250, Department of Chemical Engineering and Materials Department, University of California, Santa Barbara, Calif. 93106.

While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art and practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope. 

The invention claimed is:
 1. A filled package comprising: a vessel having a lumen defined at least in part by a wall, the wall having an interior surface facing the lumen and an outer surface; a barrier coating of SiO_(x), wherein x is from 1.5 to 2.9, from 2 to 1000 nm thick, the barrier coating of SiO_(x) having an interior surface facing the lumen and an outer surface facing the wall interior surface, the barrier coating being effective to reduce the ingress of atmospheric gas into the lumen compared to an vessel without a barrier coating; a protective coating of a saccharide, the protective coating of a saccharide having an interior surface facing the lumen and an outer surface facing the interior surface of the barrier coating, the protective coating of a saccharide being effective to increase the calculated shelf life of the package (total Si/Si dissolution rate); and a fluid composition contained in the lumen and having a pH between 5 and 9; wherein the calculated shelf life of the package is more than six months at a storage temperature of 4° C.
 2. The filled package of claim 1, in which at least a portion of the wall of the vessel comprises: a polyolefin, a polyester or a combination of a polyolefin and a polyester.
 3. The filled package of claim 1, in which at least a portion of the wall of the vessel comprises or consists essentially of a member selected from the group consisting of: a cyclic olefin polymer, a cyclic olefin copolymer, polypropylene, a polyester and polyethylene terephthalate.
 4. The filled package of claim 1, in which the vessel comprises a syringe barrel or a vial.
 5. The filled package of claim 1 in which the protective coating of a saccharide further comprises a coupling agent linking the protective coating of a saccharide to the SiO_(x) barrier coating.
 6. The filled package of claim 5, in which the protective coating of a saccharide is a sugar that is a sorbitan or comprises hyaluronic acid.
 7. The filled package of claim 5, in which the coupling agent has a functionality reactive with a saccharide hydroxyl functional group.
 8. The filled package of claim 5, in which the coupling agent comprises a member selected from the group consisting of: a silane functional group that interacts with an SiO_(x) barrier layer, trimethoxysilylpropyl isocyanate, and 3-Aminopropyltriethoxysilane (APTES).
 9. The filled package of claim 1, in which the protective coating of a saccharide contacting the fluid composition is between 10 and 1000 nm thick two years after the filled package is assembled.
 10. The filled package of claim 1, in which the rate of erosion of the protective coating of a saccharide, if directly contacted by a fluid composition having a pH of 8, is less than 20% of the rate of erosion of the barrier coating, if directly contacted by the same fluid composition under the same conditions.
 11. The filled package of claim 1, in which the rate of erosion of the protective coating of a saccharide, if directly contacted by a fluid composition having a pH of 8, is from 5% to 20% of the rate of erosion of the barrier coating, if directly contacted by the same fluid composition under the same conditions.
 12. The filled package of claim 1, in which the protective coating of a saccharide is at least coextensive with the barrier coating.
 13. The filled package of claim 1, having a shelf life, after the filled package is assembled, of at least two years, in which the shelf life is determined at 4° C.
 14. The filled package of claim 1, having a shelf life, after the filled package is assembled, of at least two years, in which the shelf life is determined at 20° C.
 15. The filled package of claim 1, in which the fluid composition removes the protective coating of a saccharide at a rate of 1 nm or less of thickness per 44 hours of contact with the fluid composition.
 16. The filled package of claim 1, in which the protective coating of a saccharide is effective to provide a lower frictional resistance than the uncoated interior surface, wherein the frictional resistance is reduced by at least 25% in comparison to the uncoated interior surface.
 17. The filled package of claim 16 which is a syringe comprising a syringe barrel and a plunger and the wall defines at least a portion of the syringe barrel, in which the protective coating of a saccharide is effective to reduce the frictional resistance between the wall and the plunger at least two years after the filled package is assembled.
 18. The filled package of claim 1, in which the silicon dissolution rate by a 50 mM potassium phosphate buffer diluted in water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. % polysorbate-80surfactant from the vessel is less than 170 ppb/day.
 19. The filled package of claim 1, in which the total silicon content of the protective coating of a saccharide and barrier coating, upon dissolution into 0.1 N potassium hydroxide aqueous solution at 40° C. from the vessel, is less than 66 ppm.
 20. The filled package of claim 1, in which the calculated shelf life (total Si/Si dissolution rate) is more than 2 years. 